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Journal articles on the topic 'Combinatory therapy'

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Author: Grafiati
Published: 10 March 2023

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1

Park, Hongsuk, Sungpil Cho, Yong Hwan Han, Margit M. Janat-Amsbury, Sihem Boudina, and You Han Bae. "Combinatory gene therapy for obesity control." Nanomedicine: Nanotechnology, Biology and Medicine 12, no. 2 (February 2016): 454. http://dx.doi.org/10.1016/j.nano.2015.12.019.

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Senichkin, V. V., G. S. Kopeina, A. V. Zamaraev, I. N. Lavrik, and B. D. Zhivotovsky. "Nutrient restriction in combinatory therapy of tumors." Molecular Biology 50, no. 3 (May 2016): 362–78. http://dx.doi.org/10.1134/s0026893316030109.

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3

Singh, Brahma N., Prateeksha, Vijai K. Gupta, Jieyin Chen, and Atanas G. Atanasov. "Organic Nanoparticle-Based Combinatory Approaches for Gene Therapy." Trends in Biotechnology 35, no. 12 (December 2017): 1121–24. http://dx.doi.org/10.1016/j.tibtech.2017.07.010.

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4

You, Mengmeng, Kangli Wang, Yongming Pan, Lingchen Tao, Quanxin Ma, Guozhi Zhang, and Fuliang Hu. "Combined royal jelly 10-hydroxydecanoic acid and aspirin has a synergistic effect against memory deficit and neuroinflammation." Food & Function 13, no. 4 (2022): 2336–53. http://dx.doi.org/10.1039/d1fo02397g.

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5

Ha, Ji-Hui, and Young-Jin Kim. "Photodynamic and Cold Atmospheric Plasma Combination Therapy Using Polymeric Nanoparticles for the Synergistic Treatment of Cervical Cancer." International Journal of Molecular Sciences 22, no. 3 (January 25, 2021): 1172. http://dx.doi.org/10.3390/ijms22031172.

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Integrating multi-modal therapies into one platform could show great promise in overcoming the drawbacks of conventional single-modal therapy and achieving improved therapeutic efficacy in cancer. In this study, we prepared pheophorbide a (Pheo a)/targeting ligand (epitope analog of oncoprotein E7, EAE7)-conjugated poly(γ-glutamic acid) (γ-PGA)/poly(lactide-co-glycolide)-block-poly(ethylene glycol) methyl ether (MPEG-PLGA)/hyaluronic acid (PPHE) polymeric nanoparticles via self-assembly and encapsulation method for the photodynamic therapy (PDT)/cold atmospheric plasma (CAP) combinatory treatment of human papillomavirus (HPV)-positive cervical cancer, thereby enhancing the therapeutic efficacy. The synthesized PPHE polymeric nanoparticles exhibited a quasi-spherical shape with an average diameter of 80.5 ± 17.6 nm in an aqueous solution. The results from the in vitro PDT efficacy assays demonstrated that PPHE has a superior PDT activity on CaSki cells due to the enhanced targeting ability. In addition, the PDT/CAP combinatory treatment more effectively inhibited the growth of cervical cancer cells by causing elevated intracellular reactive oxygen species generation and apoptotic cell death. Moreover, the three-dimensional cell culture model clearly confirmed the synergistic therapeutic efficacy of the PDT and the CAP combination therapy using PPHE on CaSki cells. Overall, these results indicate that the PDT/CAP combinatory treatment using PPHE is a highly effective new therapeutic modality for cervical cancer.
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Liu, Aiyun, Huaisong Wang, Xiaoshuang Hou, Yu Ma, Gongjun Yang, Yanglong Hou, and Ya Ding. "Combinatory antitumor therapy by cascade targeting of a single drug." Acta Pharmaceutica Sinica B 10, no. 4 (April 2020): 667–79. http://dx.doi.org/10.1016/j.apsb.2019.08.011.

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Purwati, Andang Miatmoko, Nasronudin, Eryk Hendrianto, Deya Karsari, Aristika Dinaryanti, Nora Ertanti, et al. "An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia." PLOS ONE 16, no. 6 (June 18, 2021): e0252302. http://dx.doi.org/10.1371/journal.pone.0252302.

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A potent therapy for the infectious coronavirus disease COVID-19 is urgently required with, at the time of writing, research in this area still ongoing. This study aims to evaluate the in vitro anti-viral activities of combinations of certain commercially available drugs that have recently formed part of COVID-19 therapy. Dual combinatory drugs, namely; Lopinavir-Ritonavir (LOPIRITO)-Clarithromycin (CLA), LOPIRITO-Azithromycin (AZI), LOPIRITO-Doxycycline (DOXY), Hydroxychloroquine (HCQ)-AZI, HCQ-DOXY, Favipiravir (FAVI)-AZI, HCQ-FAVI, and HCQ-LOPIRITO, were prepared. These drugs were mixed at specific ratios and evaluated for their safe use based on the cytotoxicity concentration (CC50) values of human umbilical cord mesenchymal stem cells. The anti-viral efficacy of these combinations in relation to Vero cells infected with SARS-CoV-2 virus isolated from a patient in Universitas Airlangga hospital, Surabaya, Indonesia and evaluated for IC50 24, 48, and 72 hours after viral inoculation was subsequently determined. Observation of the viral load in qRT-PCR was undertaken, the results of which indicated the absence of high levels of cytotoxicity in any samples and that dual combinatory drugs produced lower cytotoxicity than single drugs. In addition, these combinations demonstrated considerable effectiveness in reducing the copy number of the virus at 48 and 72 hours, while even at 24 hours, post-drug incubation resulted in low IC50 values. Most combination drugs reduced pro-inflammatory markers, i.e. IL-6 and TNF-α, while increasing the anti-inflammatory response of IL-10. According to these results, the descending order of effective dual combinatory drugs is one of LOPIRITO-AZI>LOPIRITO-DOXY>HCQ-AZI>HCQ-FAVI>LOPIRITO-CLA>HCQ-DOX. It can be suggested that dual combinatory drugs, e.g. LOPIRITO-AZI, can potentially be used in the treatment of COVID-19 infectious diseases.
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8

Youf, Raphaëlle, Max Müller, Ali Balasini, Franck Thétiot, Mareike Müller, Alizé Hascoët, Ulrich Jonas, et al. "Antimicrobial Photodynamic Therapy: Latest Developments with a Focus on Combinatory Strategies." Pharmaceutics 13, no. 12 (November 24, 2021): 1995. http://dx.doi.org/10.3390/pharmaceutics13121995.

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Antimicrobial photodynamic therapy (aPDT) has become a fundamental tool in modern therapeutics, notably due to the expanding versatility of photosensitizers (PSs) and the numerous possibilities to combine aPDT with other antimicrobial treatments to combat localized infections. After revisiting the basic principles of aPDT, this review first highlights the current state of the art of curative or preventive aPDT applications with relevant clinical trials. In addition, the most recent developments in photochemistry and photophysics as well as advanced carrier systems in the context of aPDT are provided, with a focus on the latest generations of efficient and versatile PSs and the progress towards hybrid-multicomponent systems. In particular, deeper insight into combinatory aPDT approaches is afforded, involving non-radiative or other light-based modalities. Selected aPDT perspectives are outlined, pointing out new strategies to target and treat microorganisms. Finally, the review works out the evolution of the conceptually simple PDT methodology towards a much more sophisticated, integrated, and innovative technology as an important element of potent antimicrobial strategies.
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Sui, Hongshu, Ningxia Ma, Ying Wang, Hui Li, Xiaoming Liu, Yanping Su, and Jiali Yang. "Anti-PD-1/PD-L1 Therapy for Non-Small-Cell Lung Cancer: Toward Personalized Medicine and Combination Strategies." Journal of Immunology Research 2018 (August 8, 2018): 1–17. http://dx.doi.org/10.1155/2018/6984948.

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Lung cancer remains a leading cause of cancer-related mortality worldwide with the poor prognosis. Encouragingly, immune checkpoint blockade targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has dramatically changed the landscape for treatments in patients with non-small-cell lung cancer (NSCLC). However, only a small proportion of NSCLC patients responded to monotherapy of anti-PD-1/PDL1 agents; together, the development of resistance to anti-PD-1/PD-L1 therapy that leads to failure of anti-PD-1/PD-L1 therapy has significantly limited a broad applicability of the findings in clinical practices. Nowadays, several companion diagnostic assays for PDL1 expression have been introduced for identifying patients who may benefit the immunotherapy. In addition, results from clinical trials explored combinatory therapeutic strategies with conventional and/or targeted therapy reported a higher efficacy with an acceptable safety profile in NSCLC treatments, as compared to the monotherapy of these agents alone. In this review article, we summarized several anti-PD-1/PD-L1 agents licensed for NSCLC treatment, with a focus on predictive biomarkers and companion diagnostic assays for identification of NSCLC patients for immunotherapy anti-PD-1/PDL1 antibodies. Of a great interest, potentials of the combinatory therapy of anti-PD-1/PDL1 therapy with a conventional or targeted therapy, or other immunotherapy such as CAR-T cell therapy were emphasized in the article.
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Xu, Ronald X., Jeff S. Xu, Tao Zuo, Rulong Shen, Tim H. Huang, and Michael F. Tweedle. "Drug-loaded biodegradable microspheres for image-guided combinatory epigenetic therapy in cells." Journal of Biomedical Optics 16, no. 2 (2011): 020507. http://dx.doi.org/10.1117/1.3548878.

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11

Shou, Kangquan, Yahui Niu, Xun Zheng, Zhanjun Ma, Chao Jian, Baiwen Qi, Xiang Hu, and Aixi Yu. "Enhancement of Bone-Marrow-Derived Mesenchymal Stem Cell Angiogenic Capacity by NPWT for a Combinatorial Therapy to Promote Wound Healing with Large Defect." BioMed Research International 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/7920265.

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Poor viability of engrafted bone marrow mesenchymal stem cells (BMSCs) often hinders their application for wound healing, and the strategy of how to take full advantage of their angiogenic capacity within wounds still remains unclear. Negative pressure wound therapy (NPWT) has been demonstrated to be effective for enhancing wound healing, especially for the promotion of angiogenesis within wounds. Here we utilized combinatory strategy using the transplantation of BMSCs and NPWT to investigate whether this combinatory therapy could accelerate angiogenesis in wounds. In vitro, after 9-day culture, BMSCs proliferation significantly increased in NPWT group. Furthermore, NPWT induced their differentiation into the angiogenic related cells, which are indispensable for wound angiogenesis. In vivo, rat full-thickness cutaneous wounds treated with BMSCs combined with NPWT exhibited better viability of the cells and enhanced angiogenesis and maturation of functional blood vessels than did local BMSC injection or NPWT alone. Expression of angiogenesis markers (NG2, VEGF, CD31, and α-SMA) was upregulated in wounds treated with combined BMSCs with NPWT. Our data suggest that NPWT may act as an inductive role to enhance BMSCs angiogenic capacity and this combinatorial therapy may serve as a simple but efficient clinical solution for complex wounds with large defects.
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Longo, Brunetti, Gnoni, Licchetta, Delcuratolo, Memeo, Solimando, and Argentiero. "Emerging role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma." Medicina 55, no. 10 (October 17, 2019): 698. http://dx.doi.org/10.3390/medicina55100698.

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Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70–80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib had been the standardcare for almost a decade until 2018 when the Food and Drug Administration approved an alternative first-line agent namely lenvatinib. Cabozantinib, regorafenib, and ramucirumab also displayed promising results in second line settings. FOLFOX4, however, results inan alternative first-line treatment for the Chineseclinical oncology guidelines. Moreover,nivolumab and pembrolizumab,two therapeutics against the Programmed death (PD)-ligand 1 (PD-L1)/PD1 axis have been recently approvedfor subsequent-line therapy. However, similar to other solid tumors, the response rate of single agent targeting PD-L1/PD1 axis is low. Therefore, a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors (ICIs), the addition of ICIs after resection or during loco-regional therapy, ICIs in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with a careful assessmentof new ICIs-based combinatory approaches.
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13

Chen, Xiaoyi, Jason Clark, Jun-lin Guan, Ashish R. Kumar, and Yi Zheng. "Susceptibility of AML to Chloroquine Therapy Is Independent of Autophagy." Blood 126, no. 23 (December 3, 2015): 1262. http://dx.doi.org/10.1182/blood.v126.23.1262.1262.

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Abstract Introduction: autophagy is a self-recycling and "waste disposal" process that maintains cellular homeostasis. Recently, the autophagy mechanism has evolved as a therapeutic target in cancer treatment due to commonly seen high autophagy activity in cancer cells and its potential role in chemoresistance. To date, inhibition of autophagy has shown therapeutic benefits in several types of solid tumors. However, whether autophagy can be a potentially effective target in AML therapy remains unclear. Here we have used autophagy gene targeted mouse models and drug inhibitors to examine the potential benefits and limitations of autophagy targeting in the treatment of AML. Methods: MLL-AF9 (MA9) oncogene transduced Atg5f/fCreER and Atg5f/fMxCre Lin- mouse bone marrow cells were used for in vitro and in vivo experiments, respectively. Autophagy activity was determined by biochemical Western Blotting and immunofluorescent microscopy against LC3 and electron microscopy (EM). Deletion of FIP200, a gene that is indispensable for both canonical and alternative autophagy pathways, was carried out similarly to further confirm the effect of autophagy-specific targeting on MA9 leukemia. Chloroquine (CQ), a late stage autophagy and lysosome inhibitor, was used at 10μM to 25μM dosages in vitro. Combinatory effects of CQ with chemotherapy, including Doxorubicin (DA) and Cytarabine (AraC), were also analyzed. CQ was also administered to mice through i.p., at 50mg/Kg, bid X 4 days. Leukemia burden, cell survival and CBC counts were analyzed after drug treatment. Results: Primary and clonal MA9 leukemia cells showed a significantly higher level of autophagy flux than normal bone marrow cells. As expected, Atg5-/- MA9 cells showed defective LC3II formation and higher p62 accumulation upon CQ treatment. However, Atg5 deletion did not cause detectable defects in proliferation or survival, or altered ROS or mitochondria levels in leukemia cells. Surprisingly, Atg5-/- MA9 leukemia cells showed reduced sensitivity to either DA or AraC treatment. Transplantation experiments showed that Atg5 deletion in vivo did not reduce leukemia burden in the bone marrow or prolong the survival of the leukemic mice, although it decreased WBC counts in peripheral blood. When examined by EM, no obvious ultrastructural difference was observed between Atg5+/+ and Atg5-/- leukemia cells and both could form endolysosomes upon CQ blockage. Although FIP200 deletion in MA9 leukemia cells caused p62 accumulation at the basal state, similar functional effects were seen as in the case of Atg5 deletion. When compared to wild type controls, FIP200-/- MA9 leukemia cells did not show any proliferation or survival disadvantage, changes in ROS accumulation or mitochondrial level. FIP200 deletion also failed to sensitize leukemia cells to chemotherapy. Finally, CQ independently suppressed leukemia cell proliferation and induced apoptosis, but it did not distinguish Atg5+/+ vs Atg5-/- or FIP200+/+ vs FIP200-/- MA9 leukemia cells in sensitivity. CQ also showed a combinatory effect with DA or AraC in inhibiting MA9 cell proliferation. Treatment of MA9 leukemia xenograft mice with CQ greatly improved anemia in the mice (P<0.01), and we are currently examining the potential effects of CQ on survival of the leukemia bearing mice. Conclusions: MA9 leukemia cells contain a high basal autophagy activity. However, autophagy-specific targeting, either through FIP200-deletion which abolishes autophagy initiation, or via Atg5-deletion which prevents autophagosome membrane elongation, does not affect the survival and proliferation of MA9 leukemia cells nor does it prolong survival of MA9 leukemia xenograft mice. These results suggest that targeting autophagy alone will unlikely produce therapeutic benefit in AML. Loss of Atg5or FIP200 does not sensitize leukemia cells to chemotherapy, further reducing the potential value of targeting autophagy in a combinatory chemotherapy scheme. Mechanistically, neither Atg5 nor FIP200 is required for proper endolysosome-formation or lysosomal degradation in leukemia cells. While CQ displayed an apparent anti-leukemic effect, it acts through an autophagy independent pathway. CQ has a combinatory effect with conventional chemotherapy drugs and may be a useful treatment regimen for MA9 mediated and other types of AML. Disclosures No relevant conflicts of interest to declare.
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Yang, Runlin, Lizhen Wang, Jie Sheng, Qianhuan Huang, Donghui Pan, Yuping Xu, Junjie Yan, Xinyu Wang, Ziyue Dong, and Min Yang. "Combinatory effects of vaccinia virus VG9 and the STAT3 inhibitor Stattic on cancer therapy." Archives of Virology 164, no. 7 (April 24, 2019): 1805–14. http://dx.doi.org/10.1007/s00705-019-04257-2.

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15

Lu, Chia-Sing, Ching-Wen Lin, Ya-Hsuan Chang, Hsuan-Yu Chen, Wei-Chia Chung, Wei-Yun Lai, Chao-Chi Ho, et al. "Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy." Journal for ImmunoTherapy of Cancer 8, no. 2 (November 2020): e001392. http://dx.doi.org/10.1136/jitc-2020-001392.

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BackgroundThe immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear.MethodsPemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo.ResultsPemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS−ROS−NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth.ConclusionsOur findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.
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Kuryk, Lukasz, Laura Bertinato, Monika Staniszewska, Katarzyna Pancer, Magdalena Wieczorek, Stefano Salmaso, Paolo Caliceti, and Mariangela Garofalo. "From Conventional Therapies to Immunotherapy: Melanoma Treatment in Review." Cancers 12, no. 10 (October 20, 2020): 3057. http://dx.doi.org/10.3390/cancers12103057.

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In this review, we discuss the use of oncolytic viruses and checkpoint inhibitors in cancer immunotherapy in melanoma, with a particular focus on combinatory therapies. Oncolytic viruses are promising and novel anti-cancer agents, currently under investigation in many clinical trials both as monotherapy and in combination with other therapeutics. They have shown the ability to exhibit synergistic anticancer activity with checkpoint inhibitors, chemotherapy, radiotherapy. A coupling between oncolytic viruses and checkpoint inhibitors is a well-accepted strategy for future cancer therapies. However, eradicating advanced cancers and tailoring the immune response for complete tumor clearance is an ongoing problem. Despite current advances in cancer research, monotherapy has shown limited efficacy against solid tumors. Therefore, current improvements in virus targeting, genetic modification, enhanced immunogenicity, improved oncolytic properties and combination strategies have a potential to widen the applications of immuno-oncology (IO) in cancer treatment. Here, we summarize the strategy of combinatory therapy with an oncolytic vector to combat melanoma and highlight the need to optimize current practices and improve clinical outcomes.
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Platoff, Rebecca M., William F. Morano, Luiz Marconcini, Nicholas DeLeo, Beth L. Mapow, Michael Styler, and Wilbur B. Bowne. "Recurrent Gastrointestinal Stromal Tumors in the Imatinib Mesylate Era: Treatment Strategies for an Incurable Disease." Case Reports in Oncological Medicine 2017 (2017): 1–8. http://dx.doi.org/10.1155/2017/8349090.

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Introduction. Recurrence of gastrointestinal stromal tumors (GISTs) after surgical resection and imatinib mesylate (IM) adjuvant therapy poses a significant treatment challenge. We present the case of a patient who underwent surgical resection after recurrence and review the current literature regarding treatment. Case Presentation. A 58-year-old man with a large intra-abdominal jejunal GIST was treated with complete surgical resection followed by IM. The patient experienced disease recurrence 3.5 years later and underwent IM dose escalation and reresection. Conclusion. Current strategies to treat recurrent GIST include dose escalation, modifying adjuvant tyrosine kinase inhibitor therapy, and surgery. High-level evidence will be required to better define the combinatory roles of tyrosine kinase inhibitor therapy, guided by molecular profiling, and surgery in the management of recurrent GIST.
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Lee, Sunghun, Bong-Woo Park, Yong Jin Lee, Kiwon Ban, and Hun-Jun Park. "In vivo combinatory gene therapy synergistically promotes cardiac function and vascular regeneration following myocardial infarction." Journal of Tissue Engineering 11 (January 2020): 204173142095341. http://dx.doi.org/10.1177/2041731420953413.

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Since myocardial infarction (MI) excessively damage the myocardium and blood vessels, the therapeutic approach for treating MI hearts should simultaneously target these two major components in the heart to achieve comprehensive cardiac repair. Here, we investigated a combinatory platform of ETV2 and Gata4, Mef2c and Tbx5 (GMT) transcription factors to develop a strategy that can rejuvenate both myocardium and vasculatures together in MI hearts. Previously ETV2 demonstrated significant effects on neovascularization and GMT was known to directly reprogram cardiac fibroblasts into cardiomyocytes under in vivo condition. Subsequently, intramyocardial delivery of a combination of retroviral GMT and adenoviral ETV2 particles into the rat MI hearts significantly increased viable myocardium area, capillary density compared to ETV2 or GMT only treated hearts, leading to improved heart function and reduced scar formation. These results demonstrate that this combinatorial gene therapy can be a promising approach to enhance the cardiac repair in MI hearts.
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Jen, Soe Hui, Melissa Poh Su Wei, and Adeline Chia Yoke Yin. "The Combinatory Effects of Glabridin and Tamoxifen on Ishikawa and MCF-7 Cell Lines." Natural Product Communications 10, no. 9 (September 2015): 1934578X1501000. http://dx.doi.org/10.1177/1934578x1501000922.

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Estrogen replacement therapy is commonly used to replace the loss of estrogen in post-menopausal women. However, it is not suitable to be used in women taking tamoxifen as both of the drugs increase the risk of endometrial cancer. This project aimed to study the potential of using the natural compound glabridin in combination with tamoxifen as a drug for estrogen replacement therapy. Ishikawa and MCF-7 cells were used to investigate the estrogenic activities stimulated by the combination of tamoxifen and glabridin through ALP and MTT assays. The expressions of the ESR1 and bcl-2 genes have also been determined using RT-PCR. The results indicated that the combination of 1×10−5M tamoxifen and 1×10−6M glabridin exhibited estrogenic activities and suppressed cell growth in both cell lines. The relative expressions of ESR1 and bcl-2 genes indicated that the estrogenicity expressed by the combinatory drug was regulated by estrogen receptor α; however, the reduction in cell proliferation was not modulated by bcl-2 anti-apoptotic proteins. These results suggested that the combination of tamoxifen and glabridin has potential to be used as an estrogen replacement drug with a reduced risk of endometrial cancer that has arisen from the intake of tamoxifen.
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Lopes-Coelho, Filipa, Filipa Martins, Sofia A. Pereira, and Jacinta Serpa. "Anti-Angiogenic Therapy: Current Challenges and Future Perspectives." International Journal of Molecular Sciences 22, no. 7 (April 5, 2021): 3765. http://dx.doi.org/10.3390/ijms22073765.

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Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.
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Ghimessy, Aron, Peter Radeczky, Viktoria Laszlo, Balazs Hegedus, Ferenc Renyi-Vamos, Janos Fillinger, Walter Klepetko, Christian Lang, Balazs Dome, and Zsolt Megyesfalvi. "Current therapy of KRAS-mutant lung cancer." Cancer and Metastasis Reviews 39, no. 4 (June 16, 2020): 1159–77. http://dx.doi.org/10.1007/s10555-020-09903-9.

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AbstractKRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRAS-related studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications.
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Hajkova, Michaela, Filip Jaburek, Bianka Porubska, Pavla Bohacova, Vladimir Holan, and Magdalena Krulova. "Cyclosporine A promotes the therapeutic effect of mesenchymal stem cells on transplantation reaction." Clinical Science 133, no. 21 (November 2019): 2143–57. http://dx.doi.org/10.1042/cs20190294.

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Abstract The successful application of mesenchymal stem cells (MSCs) remains a major challenge in stem cell therapy. Currently, several in vitro studies have indicated potentially beneficial interactions of MSCs with immunosuppressive drugs. These interactions can be even more complex in vivo, and it is in this setting that we investigate the effect of MSCs in combination with Cyclosporine A (CsA) on transplantation reaction and allogeneic cell survival. Using an in vivo mouse model, we found that CsA significantly promoted the survival of MSCs in various organs and tissues of the recipients. In addition, compared to treatment with CsA or MSCs alone, the survival of transplanted allogeneic cells was significantly improved after the combined application of MSCs with CsA. We further observed that the combinatory treatment suppressed immune response to the alloantigen challenge and modulated the immune balance by harnessing proinflammatory CD4+T-bet+ and CD4+RORγt+ cell subsets. These changes were accompanied by a significant decrease in IL-17 production along with an elevated level of IL-10. Co-cultivation of purified naive CD4+ cells with peritoneal macrophages isolated from mice treated with MSCs and CsA revealed that MSC-educated macrophages play an important role in the immunomodulatory effect observed on distinct T-cell subpopulations. Taken together, our findings suggest that CsA promotes MSC survival in vivo and that the therapeutic efficacy of the combination of MSCs with CsA is superior to each monotherapy. This combinatory treatment thus represents a promising approach to reducing immunosuppressant dosage while maintaining or even improving the outcome of therapy.
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Zhang, Zhenqing, Yunli Jia, Xiaoniu Miao, Weifeng Huang, Chao Wang, Zhijun Yuan, Wenchao Jiang, Liandi Chen, Zhiyuan Li, and Andy Tsun. "Abstract 5528: A highly potent anti-CD39 biparatopic antibody and bispecific for cancer therapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5528. http://dx.doi.org/10.1158/1538-7445.am2022-5528.

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Abstract Background: There is an increasing demand for effective combinatory agents to improve upon PD-1/PD-L1-based therapeutics. One combinatory target axis is the adenosine metabolism pathway that consists of three major players, including CD39, CD73 and A2AR. Inhibition of any of these targets have shown enhanced preclinical efficacy in combination with PD-1/PD-L1 inhibitors. CD39 is an ectonucleotidase which degrades extracellular ATP to adenosine monophosphate (AMP). This is considered a rate-limiting step for the further degradation to adenosine by CD73. Adenosine is an immunosuppressive metabolite that can suppress NK and T cells. Blockade of CD39-mediated degradation of ATP to AMP may therefore recover anti-tumor immunity through preventing the enrichment of adenosine in the tumor microenvironment. Method: Two anti-CD39 VHH molecules were generated, named Ye-37 and Ye-46, which bind to two different epitopes on CD39. Binding experiments were carried out by bio-layer interferometry. Cell binding experiments were tested on CD39-overexpression cell lines by flow cytometry. Cellular CD39 enzymatic inhibition experiments were tested using an MOLP-8 cell line and PBMC via a luminescence-based assay. Soluble CD39 enzymatic tests were carried out on recombinant CD39 protein using a similar method. T cell proliferation assays were performed and observed on CD4+ or CD8+ T cell populations. In vivo efficacy studies were tested in B-NDG B2M-KO mice that were injected subcutaneously with A375-CD39+ tumor cells and human PBMC. An anti-PD1 x CD39 bispecific antibody was then generated by fusing the anti-CD39 biparatopic antibody to the C-terminus of an anti-PD1 IgG and tested using similar methods. Results: Two candidates, Ye-37 and Ye-46, were selected for their functional activity that recognize non-overlapping epitopes on CD39. The combination of Ye-37 and Ye-46 shows high potency in cell-based and soluble CD39 assays in blocking CD39 activity. Two biparatopic molecules were generated by fusing the biparatopic unit to the N- or C-termini of Fc (46-37-Fc and Fc-37-46) and showed similar activity to the combination. In vivo, we showed single-agent control of tumor growth and potentiation of tumor-growth inhibition when combined with anti-CD73 antibodies. An anti-PD1 x CD39 bispecific was generated and showed potent inhibition of PD-1/PD-L1 interactions by cell-based assays. Potent anti-tumor efficacy was shown, which was as effective as the combination of anti-PD1 plus anti-CD39 antibodies. Conclusion: Potent anti-CD39 and anti-PD1 x CD39 therapeutic candidates have been generated with promising activity as a combinatory or single agent, respectively. As such, we plan to file for clinical trial authorization of these programs by 2022. Citation Format: Zhenqing Zhang, Yunli Jia, Xiaoniu Miao, Weifeng Huang, Chao Wang, Zhijun Yuan, Wenchao Jiang, Liandi Chen, Zhiyuan Li, Andy Tsun. A highly potent anti-CD39 biparatopic antibody and bispecific for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5528.
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Karatsai, Olena, Pavel Shliaha, Ole N. Jensen, Oleh Stasyk, and Maria Jolanta Rędowicz. "Combinatory Treatment of Canavanine and Arginine Deprivation Efficiently Targets Human Glioblastoma Cells via Pleiotropic Mechanisms." Cells 9, no. 10 (September 30, 2020): 2217. http://dx.doi.org/10.3390/cells9102217.

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Glioblastomas are the most frequent and aggressive form of primary brain tumors with no efficient cure. However, they often exhibit specific metabolic shifts that include deficiency in the biosynthesis of and dependence on certain exogenous amino acids. Here, we evaluated, in vitro, a novel combinatory antiglioblastoma approach based on arginine deprivation and canavanine, an arginine analogue of plant origin, using two human glioblastoma cell models, U251MG and U87MG. The combinatory treatment profoundly affected cell viability, morphology, motility and adhesion, destabilizing the cytoskeleton and mitochondrial network, and induced apoptotic cell death. Importantly, the effects were selective toward glioblastoma cells, as they were not pronounced for primary rat glial cells. At the molecular level, canavanine inhibited prosurvival kinases such as FAK, Akt and AMPK. Its effects on protein synthesis and stress response pathways were more complex and dependent on exposure time. We directly observed canavanine incorporation into nascent proteins by using quantitative proteomics. Although canavanine in the absence of arginine readily incorporated into polypeptides, no motif preference for such incorporation was observed. Our findings provide a strong rationale for further developing the proposed modality based on canavanine and arginine deprivation as a potential antiglioblastoma metabolic therapy independent of the blood–brain barrier.
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Schreiber, André, Benjamin Ambrosy, Oliver Planz, Sebastian Schloer, Ursula Rescher, and Stephan Ludwig. "The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs." Pharmaceutics 14, no. 9 (August 25, 2022): 1776. http://dx.doi.org/10.3390/pharmaceutics14091776.

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The coronavirus disease 2019 (COVID-19) represents a global public health burden. In addition to vaccination, safe and efficient antiviral treatment strategies to restrict the viral spread within the patient are urgently needed. An alternative approach to a single-drug therapy is the combinatory use of virus- and host-targeted antivirals, leading to a synergistic boost of the drugs’ impact. In this study, we investigated the property of the MEK1/2 inhibitor ATR-002’s (zapnometinib) ability to potentiate the effect of direct-acting antivirals (DAA) against SARS-CoV-2 on viral replication. Treatment combinations of ATR-002 with nucleoside inhibitors Molnupiravir and Remdesivir or 3C-like protease inhibitors Nirmatrelvir and Ritonavir, the ingredients of the drug Paxlovid, were examined in Calu-3 cells to evaluate the advantage of their combinatory use against a SARS-CoV-2 infection. Synergistic effects could be observed for all tested combinations of ATR-002 with DAAs, as calculated by four different reference models in a concentration range that was very well-tolerated by the cells. Our results show that ATR-002 has the potential to act synergistically in combination with direct-acting antivirals, allowing for a reduction in the effective concentrations of the individual drugs and reducing side effects.
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Miyamoto, Keiko, Motoki Watanabe, Shogen Boku, Mamiko Sukeno, Mie Morita, Haruhito Kondo, Koichi Sakaguchi, Tetsuya Taguchi, and Toshiyuki Sakai. "xCT Inhibition Increases Sensitivity to Vorinostat in a ROS-Dependent Manner." Cancers 12, no. 4 (March 30, 2020): 827. http://dx.doi.org/10.3390/cancers12040827.

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As histone deacetylase inhibitors (HDACIs) have limited efficacy against solid tumors, we investigated whether and how oxidative stress is involved in sensitivity to HDACIs to develop a novel therapeutic option of HDACIs treatment. We first tested whether a reduction of the antioxidant glutathione (GSH) by glutamine deprivation affects sensitivity to a commercially available HDACI vorinostat and reactive oxygen species (ROS) accumulation. Next we investigated the relationship between a glutamate-cystine transporter xCT and the efficacy of vorinostat using siRNA of xCT and bioinformatic analyses. Finally, we verified the combinatory effects of vorinostat and the xCT inhibitor salazosulfapyridine (SASP) on ROS accumulation, cell death induction, and colony formation. Glutamine deprivation increased vorinostat-mediated cell death with ROS accumulation. Genetic ablation of xCT improved the efficacy of vorinostat, consistent with the results of public data analyses demonstrating that xCT expressions positively correlate with insensitivity to HDACIs in many types of cancer cell lines. Vorinostat caused ROS accumulation when combined with SASP, possibly resulting in synergistic ferroptosis. Our study provides a novel mechanistic insight into the mechanism underlying sensitivity to HDACIs involving xCT, suggesting xCT to be a promising predictive marker of HDACIs and rationalizing combinatory therapy of HDACIs with xCT inhibitors to induce ferroptosis.
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Viveiros, Pedro, Ahsun Riaz, Robert J. Lewandowski, and Devalingam Mahalingam. "Current State of Liver-Directed Therapies and Combinatory Approaches with Systemic Therapy in Hepatocellular Carcinoma (HCC)." Cancers 11, no. 8 (July 31, 2019): 1085. http://dx.doi.org/10.3390/cancers11081085.

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The increasing set of liver-directed therapies (LDT) have become an integral part of hepatocellular carcinoma (HCC) treatment. These range from percutaneous ablative techniques to arterial embolization, and varied radiotherapy strategies. They are now used for local disease control, symptom palliation, and bold curative strategies. The big challenge in the face of these innovative and sometimes overlapping technologies is to identify the best opportunity of use. In real practice, many patients may take benefit from LDT used as a bridge to curative treatment such as resection and liver transplantation. Varying trans-arterial embolization strategies are used, and comparison between established and developing technologies is scarce. Also, radioembolization utilizing yttrium-90 (Y-90) for locally advanced or intermediate-stage HCC needs further evidence of clinical efficacy. There is increasing interest on LDT-led changes in tumor biology that could have implications in systemic therapy efficacy. Foremost, additional to its apoptotic and necrotic properties, LDT could warrant changes in vascular endothelial growth factor (VEGF) expression and release. However, trans-arterial chemoembolization (TACE) used alongside tyrosine-kinase inhibitor (TKI) sorafenib has had its efficacy contested. Most recently, interest in associating Y-90 and TKI has emerged. Furthermore, LDT-led differences in tumor immune microenvironment and immune cell infiltration could be an opportunity to enhance immunotherapy efficacy for HCC patients. Early attempts to coordinate LDT and immunotherapy are being made. We here review LDT techniques exposing current evidence to understand its extant reach and future applications alongside systemic therapy development for HCC.
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Fotino, C., R. D. Molano, E. Zahr, J. Molina, M. Lopez-Cabezas, G. Merizzi, A. Soleti, L. Inverardi, C. Ricordi, and A. Pileggi. "COMBINATORY ANTIOXIDANT THERAPY AND ANTI-LFA-1 ANTIBODY RESULTS IN LONG-TERM SURVIVAL OF ISLET ALLOGRAFTS." Transplantation Journal 90 (July 2010): 1013. http://dx.doi.org/10.1097/00007890-201007272-01988.

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Tochigi, Taro, Takatoshi Aoki, Yoshikane Kikushige, Tomohiko Kamimura, Takuji Yamauchi, Koji Kato, Katsuto Takenaka, Toshihiro Miyamoto, and Koichi Akashi. "Mobilization of Human Immature Hematopoietic Progenitors after Combinatory Use of Bortezomib and Immunomodulatory Drugs." Blood 126, no. 23 (December 3, 2015): 316. http://dx.doi.org/10.1182/blood.v126.23.316.316.

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Abstract Introduction: Combination of proteasome inhibitor (PI) bortezomib and immunomodulatory drugs (IMiDs), lenalidomide or thalidomide, have revealed superior outcomes in multiple myeloma (MM) over their single use. PI and IMiDs possess their direct anti-tumor activity as well as exert the indirect pleiotropic biological effects by modulating immune response, cytokine production, cell adhesion molecule, anti-apoptotic factors, cell cycle regulators. We recently found that circulating immature granulocytes and erythrocytes/megakaryocytes frequently appeared in peripheral blood (PB) in patients treated with bortezomib and IMiDs. In this study, we tested whether this effect is derived from PI, IMiDs or combination, and tried to understand its underlying mechanism to further understand their combinatory effects to normal hematopoiesis. Patients & Methods: 47 patients aged 37 - 81 years with newly diagnosed or relapsed/refractory MM were enrolled into this study. PB or bone marrow (BM) samples were collected from 7 patients treated with bortezomib/lenalidomide/dexamethasone (VRD), 15 with bortezomib/thalidomide/dexamethasone (VTD), 6 with bortezomib/dexamethasone (BD), 19 with lenalidomide/dexamethasone (RD) regimen. Clonogenic progenitor assay (CFU-C) was performed using PB samples. Change in expression level of adhesion molecules on mobilized immature cells was analyzed with flowcytometric (FCM) analysis. We counted 250 differential WBC in May-Giemsa-stained PB smears under the microscope every other day after start of chemotherapy. Result: In PB analysis, a significant fraction of immature myeloid or erythro-megakaryocyte cells was morphologically documented in 16 out of 22 (73%) patients treated with VTD/VRD, but never in the patients treated with BD or RD (n=22). During the time course, circulating immature hematopoietic cells gradually increased after the commencement of VRD or VTD therapy, and reached to a peak on a median of 12 days (range, 4 - 24 days), which was documented after 2nd or 3rd administration of bortezomib in the most patients. In these patients, a mean peak percentage of immature cells per WBC was 2.6% (0 - 6.5%) during VRD/VTD therapy. We also performed FCM analyses to confirm mobilization of immature hematopoietic progenitors in peripherally during VRD/VTD therapy. Number of mobilized CD34+ cells was statistically higher in the VRD/VTD group than that in BD/RD group (0.070% vs. 0.017%, p=0.041). We extended an analysis of change in expression of adhesion molecules on mobilized immature cells in PB mononuclear cells, since down-regulation of these molecules resulted in release of stem/progenitor cells from marrow and mobilization into the circulation. We found a significant decrease in mean fluorescence intensity (MFI) of CXCR-4 expressed on PB CD34+ cells in VRD/VTD group compared with that in BD/RD groups (11.1 vs 15.2, p=0.033). Number of CFU-cells (CFU-C) increased after 2nd or 3rd administration of bortezomib during VRD/VTD therapy compared to that before therapy (Figure), which was coincided with the appearance of immature cells in PB. A number of CFU-C derived from 100,000 PB mononuclear cells was increased up to 45 in VRD/VTD group compared to 11 in BD/RD group (p=0.021). Discussion: In this study, we unexpectedly found a transient mobilization of the immature hematopoietic progenitors in the majority of patients who received concurrently PI and IMiDs, but not in the patients treated with either alone. IMiDs promote degradation of IKZF1, which regulate GATA-1 and PU.1, critical transcription factors for erythroid and granuloid lineage, resulting in a suppression of erythropoiesis and granulocyte maturation arrest with accumulation of immature granulocyte progenitors in the BM. In contrast, PI downregulate expressions such as CXCL-12/CXCR-4 and VLA-4/VCAM-1 by which hematopoietic progenitors anchor to BM microenvironments. Therefore, we hypothesize that accumulated immature progenitors in marrow by treatment with IMiDs, can be quickly released into peripherally by concurrent administration of bortezomib. It is still unknown whether the mechanism of mobilization effect is linked to their anti-myeloma effect. Thus, our observations provided the unexpected biological effects of these drugs. Combinatory use of new drugs should be carefully evaluated to maximize their benefit or prevent possible adverse events. Figure 1. Figure 1. Disclosures Akashi: Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.
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Lin, Ching-Shwun. "Advances in Stem Cell Therapy for Erectile Dysfunction." Advances in Andrology 2014 (March 12, 2014): 1–20. http://dx.doi.org/10.1155/2014/140618.

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Stem cell (SC) therapy for erectile dysfunction (ED) has been investigated in 35 published studies, with one being a small-scale clinical trial. Out of these 35 studies, 19 are concerned with cavernous nerve (CN) injury-associated ED while 10 with diabetes mellitus- (DM-) associated ED. Adipose-derived SCs (ADSCs) were employed in 18 studies while bone marrow SCs (BMSCs) in 9. Transplantation of SCs was done mostly by intracavernous (IC) injection, as seen in 25 studies. Allogeneic and xenogeneic transplantations have increasingly been performed but their immune-incompatibility issues were rarely discussed. More recent studies also tend to use combinatory therapies by modifying or supplementing SCs with angiogenic or neurotrophic genes or proteins. All studies reported better erectile function with SC transplantation, and the majority also reported improved muscle, endothelium, and/or nerve in the erectile tissue. However, differentiation or engraftment of transplanted SCs has rarely been observed; thus, paracrine action is generally believed to be responsible for SC’s therapeutic effects. But still, few studies actually investigated and none proved paracrine action as a therapeutic mechanism. Thus, based exclusively on functional outcome data shown in preclinical studies, two clinical trials are currently recruiting patients for treatment with IC injection of ADSC and BMSC, respectively.
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31

Smits, Minke, Winald Gerritsen, and Niven Mehra. "Future therapeutic strategies for metastatic prostate cancer." Tijdschrift voor Urologie 9, no. 6-7 (September 9, 2019): 117–30. http://dx.doi.org/10.1007/s13629-019-00261-y.

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Abstract During the last decade several new therapies have been investigated and approved for metastatic prostate cancer that greatly impacts patients’ quality of life and outcome. Nevertheless, optimal sequencing algorithms are still lacking, as are combinatory strategies that deliver long-term disease stabilization. Precision medicine, utilizing molecular profiles from tissue biopsies, will help us deliver optimal patient care by identifying patients that may benefit from targeted- and immunotherapy, and help guide treatment decisions by use of predictive biomarkers. Here, we present an overview of predictive biomarkers in prostate cancer, including mismatch repair and DNA damage repair deficiency, and promising novel targeted- and immunotherapies regimens, such as PSMA-radioligand therapy, PARP inhibition and PD-1/PD-L1 and CTLA‑4 checkpoint therapy. We anticipate that these agents in monotherapy and in combination regimens will alter uro-oncological patient management within the next ten years.
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Yang, Shun-Kai, Khatijah Yusoff, Chun-Wai Mai, Wei-Meng Lim, Wai-Sum Yap, Swee-Hua Lim, and Kok-Song Lai. "Additivity vs Synergism: Investigation of the Additive Interaction of Cinnamon Bark Oil and Meropenem in Combinatory Therapy." Molecules 22, no. 11 (November 4, 2017): 1733. http://dx.doi.org/10.3390/molecules22111733.

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Hietala, Aki, Jenny Joutsen, Svea Vaarala, and Matti Säily. "A rare and complete response to combination therapy with radiation and nivolumab in a patient with metastatic urothelial cancer." BMJ Case Reports 15, no. 5 (May 2022): e246653. http://dx.doi.org/10.1136/bcr-2021-246653.

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According to the current understanding, radiotherapy can enhance the effectiveness of cancer immunotherapy due to radiation-induced release of tumour-associated antigens. Here, we present a case with a metastatic urothelial carcinoma who received nivolumab and palliative radiotherapy to a residual tumour in the vagina and to a large metastatic visceral lymph node. The treatment resulted in a rapid and virtually complete response for the time being in all metastases and in the large parailiac tumour mass. Follow up continues. The presented case demonstrates that the combinatory treatment with radiotherapy and immunotherapy can result in an exceptional response for the benefit of the patient with urothelial cancer. To our knowledge, this is one of the largest metastatic masses to disappear with a combination of immuno-oncologic (nivolumab) and radiation therapies.
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Meiler, Steffen E., Marlene Wade, Ferdane Kutlar, Shobha D. Yerigenahally, Yongjun Xue, Laure A. Moutouh-de Parseval, Laura G. Corral, Paul S. Swerdlow, and Abdullah Kutlar. "Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice." Blood 118, no. 4 (July 28, 2011): 1109–12. http://dx.doi.org/10.1182/blood-2010-11-319137.

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Abstract Pharmacologic induction of fetal hemoglobin (HbF) expression is an effective treatment strategy for sickle cell disease (SCD) and β-thalassemia. Pomalidomide is a potent structural analog of thalidomide and member of a new class of immunomodulatory drugs. Recent reports demonstrated that pomalidomide reduced or eliminated transfusion requirements in certain hematologic malignancies and induced HbF ex vivo in CD34+ progenitor cells from healthy and SCD donors. We investigated the effects of pomalidomide on erythropoiesis and hemoglobin synthesis in a transgenic mouse model of SCD. We found that 8 weeks of treatment with pomalidomide induced modest increases of HbF with similar efficacy as hydroxyurea. However, in stark contrast to hydroxyurea's myelosuppressive effects, pomalidomide augmented erythropoiesis and preserved bone marrow function. Surprisingly, combinatory therapy with both drugs failed to mitigate hydroxyurea's myelotoxic effects and caused loss of HbF induction. These findings support further evaluation of pomalidomide as a novel therapy for SCD.
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Ferri, Alessandra, Venturina Stagni, and Daniela Barilà. "Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma." International Journal of Molecular Sciences 21, no. 14 (July 11, 2020): 4910. http://dx.doi.org/10.3390/ijms21144910.

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Glioblastoma multiforme (GBM) is a severe brain tumor whose ability to mutate and adapt to therapies is at the base for the extremely poor survival rate of patients. Despite multiple efforts to develop alternative forms of treatment, advances have been disappointing and GBM remains an arduous tumor to treat. One of the leading causes for its strong resistance is the innate upregulation of DNA repair mechanisms. Since standard therapy consists of a combinatory use of ionizing radiation and alkylating drugs, which both damage DNA, targeting the DNA damage response (DDR) is proving to be a beneficial strategy to sensitize tumor cells to treatment. In this review, we will discuss how recent progress in the availability of the DDR kinase inhibitors will be key for future therapy development. Further, we will examine the principal existing DDR inhibitors, with special focus on those currently in use for GBM clinical trials.
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Mihályová, Jana, Katarína Hradská, Tomáš Jelínek, Benjamin Motais, Piotr Celichowski, and Roman Hájek. "Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders." International Journal of Molecular Sciences 22, no. 21 (October 25, 2021): 11470. http://dx.doi.org/10.3390/ijms222111470.

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Over the last few years, treatment principles have been changed towards more targeted therapy for many B-cell lymphoma subtypes and in chronic lymphocytic leukemia (CLL). Immunotherapeutic modalities, namely monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cell therapy, commonly use B-cell-associated antigens (CD19, CD20, CD22, and CD79b) as one of their targets. T-cell engagers (TCEs), a subclass of bsAbs, work on a similar mechanism as CAR-T cell therapy without the need of previous T-cell manipulation. Currently, several anti-CD20xCD3 TCEs have demonstrated promising efficacy across different lymphoma subtypes with slightly better outcomes in the indolent subset. Anti-CD19xCD3 TCEs are being developed as well but only blinatumomab has been evaluated in clinical trials yet. The results are not so impressive as those with anti-CD19 CAR-T cell therapy. Antibody-drug conjugates targeting different B-cell antigens (CD30, CD79b, CD19) seem to be effective in combination with mAbs, standard chemoimmunotherapy, or immune checkpoint inhibitors. Further investigation will show whether immunotherapy alone or in combinatory regimens has potential to replace chemotherapeutic agents from the first line treatment.
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Niska, Jared A., Jonathan H. Shahbazian, Romela Irene Ramos, Kevin P. Francis, Nicholas M. Bernthal, and Lloyd S. Miller. "Vancomycin-Rifampin Combination Therapy Has Enhanced Efficacy against an Experimental Staphylococcus aureus Prosthetic Joint Infection." Antimicrobial Agents and Chemotherapy 57, no. 10 (August 5, 2013): 5080–86. http://dx.doi.org/10.1128/aac.00702-13.

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ABSTRACTTreatment of prosthetic joint infections often involves a two-stage exchange, with implant removal and antibiotic spacer placement followed by systemic antibiotic therapy and delayed reimplantation. However, if antibiotic therapy can be improved, one-stage exchange or implant retention may be more feasible, thereby decreasing morbidity and preserving function. In this study, a mouse model of prosthetic joint infection was used in whichStaphylococcus aureuswas inoculated into a knee joint containing a surgically placed metallic implant extending from the femur. This model was used to evaluate whether combination therapy of vancomycin plus rifampin has increased efficacy compared with vancomycin alone against these infections. On postoperative day 7, vancomycin with or without rifampin was administered for 6 weeks with implant retention.In vivobioluminescence imaging,ex vivoCFU enumeration, X-ray imaging, and histologic analysis were carried out. We found that there was a marked therapeutic benefit when vancomycin was combined with rifampin compared with vancomycin alone. Taken together, our results suggest that the mouse model used could serve as a valuablein vivopreclinical model system to evaluate and compare efficacies of antibiotics and combinatory therapy for prosthetic joint infections before more extensive studies are carried out in human subjects.
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Martínez-Moreno, Carlos, Denisse Calderón-Vallejo, Steve Harvey, Carlos Arámburo, and José Quintanar. "Growth Hormone (GH) and Gonadotropin-Releasing Hormone (GnRH) in the Central Nervous System: A Potential Neurological Combinatory Therapy?" International Journal of Molecular Sciences 19, no. 2 (January 26, 2018): 375. http://dx.doi.org/10.3390/ijms19020375.

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Kim, Julius, Benjamin Kong, Tsun-Ho Lo, Michael S. Papadimitrous, Jennifer Hsu, Phillip Fromm, Kimberley Kaufman, Michael Buckland, Georgina Clark, and Derek Hart. "EXTH-46. A COMBINATORY IMMUNOTHERAPY AGAINST BRAIN TUMOUR: BLOOD DENDRITIC CELL BASED VACCINE THERAPY WITH CHECKPOINT INHIBITOR(S)." Neuro-Oncology 20, suppl_6 (November 2018): vi94—vi95. http://dx.doi.org/10.1093/neuonc/noy148.394.

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Qu, G. J., D. X. Ouyang, A. X. An, L. Zhang, B. Chen, J. Cai, and H. Q. X. Li. "Developing a series of Kras/P53 compound mutant mouse allograft tumor models for combinatory target- and immuno-therapy." European Journal of Cancer 69 (December 2016): S112. http://dx.doi.org/10.1016/s0959-8049(16)32932-x.

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Yang, Qianhao, Haohao Yin, Tianming Xu, Daoyu Zhu, Junhui Yin, Yixuan Chen, Xiaowei Yu, et al. "Engineering 2D Mesoporous Silica@MXene‐Integrated 3D‐Printing Scaffolds for Combinatory Osteosarcoma Therapy and NO‐Augmented Bone Regeneration." Small 16, no. 14 (April 2020): 1906814. http://dx.doi.org/10.1002/smll.201906814.

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Chung, Chih Kit, C. G. Da Silva, Dana Kralisch, Alan Chan, Ferry Ossendorp, and Luis J. Cruz. "Combinatory therapy adopting nanoparticle-based cancer vaccination with immune checkpoint blockade for treatment of post-surgical tumor recurrences." Journal of Controlled Release 285 (September 2018): 56–66. http://dx.doi.org/10.1016/j.jconrel.2018.07.011.

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43

Schmitz, Thomas, Ajay Abisheck Paul George, Britta Nubbemeyer, Charlotte A. Bäuml, Torsten Steinmetzer, Oliver Ohlenschläger, Arijit Biswas, and Diana Imhof. "NMR-Based Structural Characterization of a Two-Disulfide-Bonded Analogue of the FXIIIa Inhibitor Tridegin: New Insights into Structure–Activity Relationships." International Journal of Molecular Sciences 22, no. 2 (January 17, 2021): 880. http://dx.doi.org/10.3390/ijms22020880.

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The saliva of blood-sucking leeches contains a plethora of anticoagulant substances. One of these compounds derived from Haementeria ghilianii, the 66mer three-disulfide-bonded peptide tridegin, specifically inhibits the blood coagulation factor FXIIIa. Tridegin represents a potential tool for antithrombotic and thrombolytic therapy. We recently synthesized two-disulfide-bonded tridegin variants, which retained their inhibitory potential. For further lead optimization, however, structure information is required. We thus analyzed the structure of a two-disulfide-bonded tridegin isomer by solution 2D NMR spectroscopy in a combinatory approach with subsequent MD simulations. The isomer was studied using two fragments, i.e., the disulfide-bonded N-terminal (Lys1–Cys37) and the flexible C-terminal part (Arg38–Glu66), which allowed for a simplified, label-free NMR-structure elucidation of the 66mer peptide. The structural information was subsequently used in molecular modeling and docking studies to provide insights into the structure–activity relationships. The present study will prospectively support the development of anticoagulant-therapy-relevant compounds targeting FXIIIa.
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Zhang, Xin, Huiqin Li, Xiupeng Lv, Li Hu, Wen Li, Meiting Zi, and Yonghan He. "Impact of Diets on Response to Immune Checkpoint Inhibitors (ICIs) Therapy against Tumors." Life 12, no. 3 (March 11, 2022): 409. http://dx.doi.org/10.3390/life12030409.

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Immunotherapy has revolutionized the established therapeutics against tumors. As the major immunotherapy approach, immune checkpoint inhibitors (ICIs) achieved remarkable success in the treatment of malignancies. However, the clinical gains are far from universal and durable, because of the primary and secondary resistance of tumors to the therapy, or side effects induced by ICIs. There is an urgent need to find safe combinatorial strategies that enhance the response of ICIs for tumor treatment. Diets have an excellent safety profile and have been shown to play pleiotropic roles in tumor prevention, growth, invasion, and metastasis. Accumulating evidence suggests that dietary regimens bolster not only the tolerability but also the efficacy of tumor immunotherapy. In this review, we discussed the mechanisms by which tumor cells evade immune surveillance, focusing on describing the intrinsic and extrinsic mechanisms of resistance to ICIs. We also summarized the impacts of different diets and/or nutrients on the response to ICIs therapy. Combinatory treatments of ICIs therapy with optimized diet regimens own great potential to enhance the efficacy and durable response of ICIs against tumors, which should be routinely considered in clinical settings.
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Shah, Syed, Deming Zhao, Giulio Taglialatela, Tariq Hussain, Haodi Dong, Naveed Sabir, Mazhar Mangi, et al. "Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway." International Journal of Molecular Sciences 20, no. 5 (March 6, 2019): 1144. http://dx.doi.org/10.3390/ijms20051144.

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Transcription factors play a significant role during the symptomatic onset and progression of prion diseases. We previously showed the immunomodulatory and nuclear factor of activated T cells’ (NFAT) suppressive effects of an immunosuppressant, FK506, in the symptomatic stage and an antibiotic, minocycline, in the pre-symptomatic stage of prion infection in hamsters. Here we used for the first time, a combinatory FK506+minocycline treatment to test its transcriptional modulating effects in the symptomatic stage of prion infection. Our results indicate that prolonged treatment with FK506+minocycline was effective in alleviating astrogliosis and neuronal death triggered by misfolded prions. Specifically, the combinatory therapy with FK506+minocycline lowered the expression of the astrocytes activation marker GFAP and of the microglial activation marker IBA-1, subsequently reducing the level of pro-inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), and increasing the levels of anti-inflammatory cytokines IL-10 and IL-27. We further found that FK506+minocycline treatment inhibited mitogen-activated protein kinase (MAPK) p38 phosphorylation, NF-kB nuclear translocation, caspase expression, and enhanced phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated Bcl2-associated death promoter (pBAD) levels to reduce cognitive impairment and apoptosis. Interestingly, FK506+minocycline reduced mitochondrial fragmentation and promoted nuclear factor–erythroid2-related factor-2 (NRF2)-heme oxygenase 1 (HO-1) pathway to enhance survival. Taken together, our results show that a therapeutic cocktail of FK506+minocycline is an attractive candidate for prolonged use in prion diseases and we encourage its further clinical development as a possible treatment for this disease.
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46

Franson, Andrea, Cassie Kline, Annette Molinaro, Yalan Zhang, Kelly Hitchner, Carl Koschmann, Javad Nazarian, and Sabine Mueller. "DIPG-09. Diffuse Midline Glioma-Adaptive Combinatory Trial (DMG-ACT): A biology-driven platform trial in pediatric and young adult patients with diffuse midline glioma." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i19. http://dx.doi.org/10.1093/neuonc/noac079.066.

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Abstract BACKGROUND: Despite advances in our understanding of the biology of diffuse midline gliomas (DMGs), little progress has been made in improving outcomes. Therapy development is limited by lack of preclinical data across multiple model systems and laboratories; limited knowledge about blood-brain barrier penetrance; and lack of multi-agent therapies. We aim to address these issues through DMG-ACT, where we translate robust preclinical data using ONC201 as the therapy backbone in a multi-arm, combination strategy within an innovative trial design. DESIGN: DMG-ACT is an open-label, multi-institutional trial of combination therapy for patients with DMG between 2 and 39 years of age. The trial utilizes a novel Bayesian drug combination platform design with adaptive shrinkage (ComPAS). ComPAS allows ongoing assessment of therapy efficacy with borrowing of data across different arms and the ability to eliminate ineffective drug combinations and add new promising combinations throughout the trial. ONC201 is the backbone therapy in each arm and given in combination with other agents that show additive or synergistic benefit in preclinical testing. Patients enter into one of three cohorts: newly diagnosed (Cohort 1), post-radiation (Cohort 2), and relapsed/progressive (Cohort 3). The cohorts offer a target validation option to assess intratumoral pharmacokinetics and pharmacodynamics of drug given prior to tumor biopsy. Cohort 1 and 3 offer radiation or re-irradiation with concomitant single agent therapy followed by maintenance combination therapy. The primary efficacy endpoints are median progression-free survival at 6 months (Cohort 1 and 2) and overall survival at 7 months (Cohort 3). Exploratory endpoints include intratumoral drug concentration, toxicity profile of combination therapy during radiation therapy, toxicity profile and efficacy of combination therapy, CSF and ctDNA analysis, and health related quality of life, cognitive, and patient/proxy-reported outcome measures. This trial was successfully launched in November 2021 with updates to be presented at the meeting.
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47

Franson, Andrea, Cassie Kline, Annette Molinaro, Yalan Zhang, Kelly Hitchner, Nalin Gupta, Carl Koschmann, Michael Prados, Javad Nazarian, and Sabine Mueller. "CTNI-09. DIFFUSE MIDLINE GLIOMA-ADAPTIVE COMBINATORY TRIAL (DMG-ACT): A COMBINATION PLATFORM TRIAL IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii71—vii72. http://dx.doi.org/10.1093/neuonc/noac209.275.

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Abstract Despite advances in understanding the biology of diffuse midline gliomas (DMGs), clinical outcomes have not significantly improved. Therapy development is limited by: lack of preclinical data across multiple models and laboratories, limited knowledge about blood-brain barrier penetrance, and lack of multi-agent therapeutic approaches. We aimed to address these limitations by designing and implementing an innovative platform clinical trial (DMG-ACT). DMG-ACT is an open-label, multi-institutional, international trial of combination therapy for patients with DMG between 2 and 39 years of age. This study utilizes a novel Bayesian drug combination platform design with adaptive shrinkage (ComPAS). ComPAS allows for ongoing assessment of therapy efficacy with data borrowing across arms and the ability to eliminate ineffective drug combinations and add new promising combinations throughout the trial. The current treatment arms include ONC201 in combination with paxalisib. Patients enter one of three cohorts: newly-diagnosed (Cohort 1), post-radiation (Cohort 2), and relapsed/progressive (Cohort 3). Each cohort offers a target validation phase for patients who have not yet undergone biopsy to assess intratumoral pharmacokinetics/pharmacodynamics of pre-biopsy, single-agent dosing. Cohorts 1 and 3 offer radiation (Cohort 1) or re-irradiation (Cohort 3) with concomitant single-agent therapy followed by maintenance with combination therapy. The primary efficacy endpoints are median progression-free survival at 6 months (Cohorts 1 and 2) and overall survival at 7 months (Cohort 3). Exploratory endpoints include intratumoral drug concentrations; toxicity profile of combination therapy during radiation; toxicity profile and efficacy of combination therapy; CSF, ctDNA, stool, and flow cytometry biomarker analyses; and health related quality of life, cognitive, and patient/proxy-reported outcome measures. Additional therapy combinations that have shown additive or synergistic benefit in preclinical testing will be incorporated in future trial iterations and several are currently in development. The trial was launched in October 2021, with a total of 21 patients enrolled as of May 2022.
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48

Cortese, Barbara, Stefania D’Amone, Mariangela Testini, Patrizia Ratano, and Ilaria Elena Palamà. "Hybrid Clustered Nanoparticles for Chemo-Antibacterial Combinatorial Cancer Therapy." Cancers 11, no. 9 (September 10, 2019): 1338. http://dx.doi.org/10.3390/cancers11091338.

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Background: A great number of therapeutic limitations, such as chemoresistance, high dosage, and long treatments, are still present in cancer therapy, and are often followed by side effects such as infections, which represent the primary cause of death among patients. Methods: We report pH- and enzymatic-responsive hybrid clustered nanoparticles (HC-NPs), composed of a PCL polymeric core loaded with an anticancer drug, such as Imatinib Mesylate (IM), and coated with biodegradable multilayers embedded with antibacterial and anticancer baby-ship silver NPs, as well as a monoclonal antibody for specific targeting of cancer cells conjugated on the surface. Results: The HC-NPs presented an onion-like structure that serially responded to endogenous stimuli. After internalization into targeted cancer cells, the clustered nanoparticles were able to break up, thanks to intracellular proteases which degraded the biodegradable multilayers and allowed the release of the baby-ship NPs and the IM loaded within the pH-sensible polymer present inside the mothership core. In vitro studies validated the efficiency of HC-NPs in human chronic leukemic cells. This cellular model allowed us to demonstrate specificity and molecular targeting sensitivity, achieved by using a combinatorial approach inside a single nano-platform, instead of free administrations. The combinatory effect of chemotherapic drug and AgNPs in one single nanosystem showed an improved cell death efficacy. In addition, HC-NPs showed a good antibacterial capacity on Gram-negative and Gram-positive bacteria. Conclusions: This study shows an important combinatorial anticancer and antimicrobial effect in vitro.
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49

Hillmann, Petra, Justin A. Selvaraj, Sina E. Zimmerli, Pascale G. Birrer, Claudia C. Bohnert, Klaas P. Zuideveld, Stefan J. Scherer, and Friedrich Metzger. "Abstract 1081: Design of combinatory RNA molecules to simultaneously activate tumor immunity and target several signaling pathways in solid tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1081. http://dx.doi.org/10.1158/1538-7445.am2022-1081.

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Abstract Combination therapy is implicated for many oncological indications to circumvent resistance mechanisms that reduce efficacy of targeted drugs. In recent years, mRNA has been successfully utilized preclinically to deliver cytokines to tumors locally at efficacious doses. Versameb has developed a technology platform which enables combinatorial approaches for intra-tumoral application of nucleotide therapeutics that comprise an mRNA element covalently linked to up to three independent siRNA elements targeting various tumor-relevant genes. Such constructs allow a dose-synchronized treatment of different components in parallel, which opens the opportunity to address up to four cancer targets within a single RNA molecule. For proof of concept, we designed a combinatory molecule consisting of mRNA coding for human interleukin 2 (IL-2) linked to a small interfering RNA (siRNA) targeting vascular endothelial growth factor A (VEGFA). Transfection of A549 adenocarcinoma cells led to dose-dependent secretion of efficacious concentrations of IL-2 and simultaneous complete VEGFA knockdown. IL-2 protein functionality was tested in SK-OV-3 cell spheroids co-cultured with human primary peripheral blood mononuclear cells (PBMCs). After treatment, secreted IL-2 protein induced immune cell activation and consecutive spheroid killing by PBMCs from three independent donors. VEGFA functionality was tested in an in vitro vascularization assay in HUVEC cells. Cells were treated with supernatants of vehicle or RNA transfected SCC-4 head & neck cancer cells producing high endogenous VEGFA, and vascular sprouting was analyzed quantitatively. While vehicle-treated cell supernatant induced vessel sprouting, supernatant from RNA treated cells showed much reduced sprouting in vitro consistent with the lower VEGFA levels measured, confirming functionality of the siRNA effect on VEGFA protein expression. We further provide examples of combinatory molecules targeting up to 4 independent key cancer hallmarks and their functional outcomes in various cancer cell types. In conclusion, mRNA combination constructs can be developed into cancer therapeutics that target several pro-tumorigenic pathways simultaneously with a single molecule overcoming hurdles of delivery, toxicity, and regulatory requirements for combination therapies. Citation Format: Petra Hillmann, Justin A. Selvaraj, Sina E. Zimmerli, Pascale G. Birrer, Claudia C. Bohnert, Klaas P. Zuideveld, Stefan J. Scherer, Friedrich Metzger. Design of combinatory RNA molecules to simultaneously activate tumor immunity and target several signaling pathways in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1081.
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Bader, Sina, Julia Wilmers, Martin Pelzer, Verena Jendrossek, and Justine Rudner. "Activation of anti-oxidant Keap1/Nrf2 pathway modulates efficacy of dihydroartemisinin-based monotherapy and combinatory therapy with ionizing radiation." Free Radical Biology and Medicine 168 (May 2021): 44–54. http://dx.doi.org/10.1016/j.freeradbiomed.2021.03.024.

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