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Автор: Grafiati

Опубліковано: 10 грудня 2022

Оновлено: 29 січня 2023

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1

Harms, Julia K., Tet-Woo Lee, Tao Wang, Amy Lai, Dennis Kee, John M. Chaplin, Nick P. McIvor, et al. "Impact of Tumour Hypoxia on Evofosfamide Sensitivity in Head and Neck Squamous Cell Carcinoma Patient-Derived Xenograft Models." Cells 8, no. 7 (July 13, 2019): 717. http://dx.doi.org/10.3390/cells8070717.

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Tumour hypoxia is a marker of poor prognosis and failure of chemoradiotherapy in head and neck squamous cell carcinoma (HNSCC), providing a strategy for therapeutic intervention in this setting. To evaluate the utility of the hypoxia-activated prodrug evofosfamide (TH-302) in HNSCC, we established ten early passage patient-derived xenograft (PDX) models of HNSCC that were characterised by their histopathology, hypoxia status, gene expression, and sensitivity to evofosfamide. All PDX models closely resembled the histology of the patient tumours they were derived from. Pimonidazole-positive tumour hypoxic fractions ranged from 1.7–7.9% in line with reported HNSCC clinical values, while mRNA expression of the Toustrup hypoxia gene signature showed close correlations between PDX and matched patient tumours, together suggesting the PDX models may accurately model clinical tumour hypoxia. Evofosfamide as a single agent (50 mg/kg IP, qd × 5 for three weeks) demonstrated antitumour efficacy that was variable across the PDX models, ranging from complete regressions in one p16-positive PDX model to lack of significant activity in the three most resistant models. Despite all PDX models showing evidence of tumour hypoxia, and hypoxia being essential for activation of evofosfamide, the antitumour activity of evofosfamide only weakly correlated with tumour hypoxia status determined by pimonidazole immunohistochemistry. Other candidate evofosfamide sensitivity genes—MKI67, POR, and SLFN11—did not strongly influence evofosfamide sensitivity in univariate analyses, although a weak significant relationship with MKI67 was observed, while SLFN11 expression was lost in PDX tumours. Overall, these data confirm that evofosfamide has antitumour activity in clinically-relevant PDX tumour models of HNSCC and support further clinical evaluation of this drug in HNSCC patients. Further research is required to identify those factors that, alongside hypoxia, can influence sensitivity to evofosfamide and could act as predictive biomarkers to support its use in precision medicine therapy of HNSCC.

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2

O'Connor, Liam J., Cindy Cazares-Körner, Jaideep Saha, Charles N. G. Evans, Michael R. L. Stratford, Ester M. Hammond, and Stuart J. Conway. "Efficient synthesis of 2-nitroimidazole derivatives and the bioreductive clinical candidate Evofosfamide (TH-302)." Organic Chemistry Frontiers 2, no. 9 (2015): 1026–29. http://dx.doi.org/10.1039/c5qo00211g.

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3

Jayaprakash, Priyamvada, Meghan Rice, Krithikaa Rajkumar Bhanu, Brittany Morrow, Joseph Marszalek, Jason Gay, Christopher Vellano, Benjamin Cowen, Dean Welsch, and Michael Curran. "622 Disrupted oxygen supply and tumor hyper- oxygen consumption contribute independently to prostate cancer immune privilege." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A652. http://dx.doi.org/10.1136/jitc-2021-sitc2021.622.

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BackgroundDespite the success of immunotherapy in immune-infiltrated ”hot” tumors like melanoma, ”cold” tumors like prostate cancer remain unresponsive [1,2,3]. We find that these tumors harbor regions of hypoxia that act as islands of immune privilege that exclude T cells, while retaining immunosuppressive myeloid cells. Targeting hypoxia using the hypoxia-activated prodrug, TH-302 (Evofosfamide) reduced hypoxic regions and co-operated with immune checkpoint blockade (anti-CTLA-4+anti PD-1) to drive tumor regression in transplantable and spontaneous murine prostate tumors [4]. In a Phase I clinical trial, the combination of Evofosfamide and anti CTLA-4 (Ipilimumab) elicited both objective responses and prolonged disease stabilization in late-stage ”cold” tumor patients. However, Evofosfamide reduces but does not eliminate hypoxia and patient tumors resistant to treatment with Evofosfamide and Ipilimumab were hyper-metabolic [5]. Heightened tumor oxidative metabolism has been shown to generate hypoxic zones that resist PD-1 blockade therapy [6] and treatment with Metformin, a mitochondrial complex I inhibitor may reduce hypoxia and improve responses [7]. We hypothesized that targeting tumor oxidative metabolism using mitochondrial complex I inhibitors might diminish tumor hypoxia and, in conjunction with Evofosfamide, sensitize unresponsive tumors to immunotherapy.MethodsWe investigated the capacity of two mitochondrial complex I inhibitors to reduce tumor oxidative metabolism, diminish myeloid suppressive capacity and improve anti-tumor T cell immunity, alone and in combination with Evofosfamide and checkpoint blockade. We assessed tumor burden and immune composition and characterized metabolic profiles using Seahorse XFe96 analyzer (Agilent).ResultsWhile Evofosfamide or inhibition of oxidative metabolism alone did not significantly impact tumor regression, dual combination and triple combination with checkpoint blockade led to a significant reduction in tumor burden. Assessment of the tumor immune microenvironment identified improvements in CD8 and CD4 effector T cell proliferation. In vitro metabolic and functional profiling of TRAMP-C2 prostate tumors, pre-activated T cells and myeloid derived suppressor cells revealed differential effects of complex I inhibition, with inhibition resulting in reduced tumor proliferation and myeloid suppressive function but increases in proliferation and cytotoxic function of pre-activated T cells.ConclusionsOur findings indicate that tumor hypoxia and associated immune suppressive programming can be reduced through both local tissue remodeling and limitation of tumor oxygen metabolism. Complex I inhibition selectively inhibits tumor and myeloid cell function, while sparing T cells. This provides opportunities to craft synergistic immuno-metabolic therapies with the potential to treat ”cold” tumor patients refractory to current FDA approved immunotherapeutics.ReferencesCurran MA, Montalvo W, Yagita H, and Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010; 107(9): 4275–80.Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013; 369(2): 122–33.Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, doubleblind, phase 3 trial. Lancet Oncol. 2014;15(7):700–12.Jayaprakash P, Ai M, Liu A, Budhani P, Bartkowiak T, Sheng J, et al. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J Clin Invest. 2018; 128 (11): 5137–5149.Hegde A, Jayaprakash P, Couillault CA, Piha-Paul S, Karp D, Rodon J, et al. A Phase I Dose-Escalation Study to Evaluate the Safety and Tolerability of Evofosfamide in Combination with Ipilimumab in Advanced Solid Malignancies. Clin Cancer Res. 2021; 27(11): 3050–3060.Najjar YG, Menk AV, Sander C, Rao U, Karunamurthy A, Bhatia R, et al. Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma. JCI Insight. 2019 4(5): e124989. A.Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia. Cancer Immunol Res. 2017; 5(1):9–16.

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4

Grande, Enrique, Daniel E. Castellano, Ana B. Custodio, Rocio Garcia-Carbonero, Encarnación González, Carlos López-López, Javier Munarriz, et al. "A phase II trial to assess the activity and safety of the hypoxia-activated prodrug evofosfamide (TH-302) in combination with sunitinib in patients with disseminated grade 1 and 2 pancreatic neuroendocrine tumors (pNET) as a first-line approach: The GETNE-1408 trial." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): TPS479. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.tps479.

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TPS479 Background: Pancreatic-NETs are highly vascular tumors. The anti-angiogenetic sunitinib was approved in advanced pNETs based on prolongation of progression-free survival. Upregulation of several proangiogenic factors that reflects intratumor hypoxia conditions might drive resistance to sunitinib in pNETs. Evofosfamide is a prodrug that under hypoxic conditions preferentially releases a brominated version of isophosphoramide mustard and has shown activity in cell lines from neural crest derived tumors such as melanoma and glioblastoma/astrocytoma. We hypothesize that evofosfamide may have activity in the pathologic hypoxic conditions present in the tumor environment of neuroendocrine tumors inducing responses that may be consolidated and prolonged with sunitinib in patients with advanced pNETs that are naïve for systemic treatment. Methods: This is a prospective, non randomized, open-label, phase II study that is being conducted in 10 university sites belonging to the Spanish Task Force Group for NETs (GETNE) in Spain. Patients with histologically proven diagnosis of progressive unresectable or metastatic pNET with Ki67 < 20% and grade 1 or 2 will receive sunitinib orally at 37.5 mg PO daily on days 1 to 28 of a 28-day cycle (4 weeks) plus evofosfamide administered at 340 mg/m2 by IV infusion over 30-60 minutes on Days 8, 15 and 22 of a 28-day cycle (4 weeks). Hypoxia-related tumor markers, single nucleotide polymorphisms related to activity and metabolism of antiangiogenic agents (VEGFR2, VEGFR3, PDGFR-α, VEGF-A, IL8, CYP3A4, CYP3A5, ABCB1-2) will be correlated with clinical outcome. In this study it is planned to include 43 patientsbased on a two-stage Simon’s phase II design (α = 0.05, β = 80%). If the trial shows 8 responses or more among 43 patients, the treatment will be considered for further investigation. EudraCT number: 2014-004072-30 Clinical trial information: NCT02402062.

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5

Bailleul, Quentin, Pauline Navarin, Mélanie Arcicasa, Christine Bal-Mahieu, Angel Montero Carcaboso, Xuefen Le Bourhis, Alessandro Furlan, Samuel Meignan, and Pierre Leblond. "Evofosfamide Is Effective against Pediatric Aggressive Glioma Cell Lines in Hypoxic Conditions and Potentiates the Effect of Cytotoxic Chemotherapy and Ionizing Radiations." Cancers 13, no. 8 (April 9, 2021): 1804. http://dx.doi.org/10.3390/cancers13081804.

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Hypoxia is a hallmark of many solid tumors and is associated with resistance to anticancer treatments. Hypoxia-activated prodrugs (HAPs) were developed to target the hypoxic regions of these tumors. Among 2nd generation HAPs, Evofosfamide (Evo, also known as TH-302) exhibits preclinical and clinical activities against adult glioblastoma. In this study, we evaluated its potential in the field of pediatric neuro-oncology. We assessed the efficacy of Evo in vitro as a single drug, or in combination with SN38, doxorubicin, and etoposide, against three pediatric high-grade glioma (pHGG) and three diffuse intrinsic pontine glioma (DIPG) cell lines under hypoxic conditions. We also investigated radio-sensitizing effects using clonogenic assays. Evo inhibited the growth of all cell lines, mainly under hypoxia. We also highlighted a significant synergism between Evo and doxorubicin, SN38, or etoposide. Finally, Evo radio-sensitized the pHGG cell line tested, both with fractionated and single-dose irradiation schedules. Altogether, we report here the first preclinical proof of evidence about Evofosfamide efficiency against hypoxic pHGG and DIPG cells. Since such tumors are highly hypoxic, and Evo potentiates the effect of ionizing radiation and chemotherapy, it appears as a promising therapeutic strategy for children with brain tumors.

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6

Laubach, Jacob P., Noopur Raje, Andrew J. Yee, Philippe Armand, Robert L. Schlossman, Jacalyn Rosenblatt, Michael G. Martin, et al. "Final Results of a Phase 1/2 Open-Label Study to Assess the Safety, Tolerability and Preliminary Efficacy of Evofosfamide, a Hypoxia-Activated Prodrug, and Dexamethasone with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma." Blood 128, no. 22 (December 2, 2016): 2122. http://dx.doi.org/10.1182/blood.v128.22.2122.2122.

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Abstract Purpose: This phase 1/2 study was conducted to determine the maximum tolerated dose (MTD), safety, tolerability, and clinical activity of the hypoxia-activated prodrug evofosfamide (TH-302) and dexamethasone with or without bortezomib in relapsed/refractory multiple myeloma. Patients & Methods: Patients were enrolled to stage A (evofosfamide + dexamethasone) followed by stage B (evofosfamide + bortezomib + dexamethasone). Stage A enrollment began in March 2012 and ended in May 2014. In total 34 patients were enrolled to stage A, with 31 patients being treated. Stage B enrollment began in June 2014 and ended in July 2015. In total 28 patients were enrolled and treated on stage B. Patients enrolled on study were diagnosed with relapsed/ refractory multiple myeloma (RRMM), had adequate hepatic, renal, and hematologic function, as well as an ECOG performance status of ≤2, and had all received at least 2 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. In stage B, patients previously receiving bortezomib must not have discontinued due to toxicity. Patients must have had measureable disease as determined by the International Working Group (IMWG) criteria. In stage A, evofosfamide was administered IV in conjunction with a fixed oral dose of 40 mg dexamethasone on Days 1, 4, 8 and 11 of a 21-day cycle. In stage B, evofosfamide was administered in conjunction with a fixed oral dose of 40 mg dexamethasone and a fixed IV or SC dose of 1.3 mg/m2 bortezomib. Stage A dose escalation began at a dose of 240 mg/m2 evofosfamide and increased stepwise in a 3+3 design until reaching the MTD of 480 mg/m2. The recommended phase 2 dose (RP2D) was set at 340 mg/m2 and a dose expansion cohort of 15 treated patients were treated at the RP2D. Stage B dose escalation began at a dose of 240 mg/m2 and concluded at the 340 mg/m2 RP2D of stage A. There were no DLTs observed in this cohort. A total of 24 patients were treated at the RP2D. Results: Of the 31 patients treated on stage A, the median age was 65, with a range of 53-86. The median number of prior treatments was 6 (range: 2-13). Of the 28 patients treated on stage B, the median age was 62, with a range of 45-83. The median number of prior treatments was 8 (range: 3 - 16). All patients had prior bortezomib exposure with a median number of bortezomib containing regimens in stage B of 3 (range: 1-6). The most common stage A grade 3/4 events were anemia (36%), neutropenia (32%), thrombocytopenia (39%), leukopenia (23%), cellulitis (10%) and pneumonia (10%). Four pts (13%) discontinued due to an adverse event. The most common Arm B grade 3/4 events were thrombocytopenia (61%), neutropenia (32%), anemia (25%), leukopenia (18%) and pneumonia (14%). Two patients (7%) discontinued due to an adverse event. Of the 31 patients evaluable for response in stage A, 4 Partial Responses and 2 Minimal Responses were reported for a clinical benefit rate of 19%. Twenty patients (65%) in stage A had stable Disease. Of the 28 patients evaluable for response in stage B, 1 Complete Response, 2 Partial Responses and 2 Minimal Responses were reported for a clinical benefit rate of 18%. Eighteen patients (64%) in stage B had Stable Disease. Conclusion: A 340 mg/m2 twice a week dose of the hypoxia- activated agent evofosfamide was established as the recommended Phase 2 dose when combined with dexamethasone with or without bortezomib. Clinical activity was noted along with a majority of patients having stable disease or better even in this heavily pre-treated refractory population of MM. The use of hypoxia-activated agents holds promise as a novel therapeutic target in MM. Disclosures Raje: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding. Armand:Pfizer: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Sequenta Inc: Research Funding; Merck: Consultancy, Research Funding. Rosenblatt:BMS: Research Funding; Astex: Research Funding; DCPrime: Research Funding. Shain:Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Anderson:Oncopep: Other: Scientific Founder; Onyx: Membership on an entity's Board of Directors or advisory committees; Acetylon: Other: Scientific Founder; Sonofi Aventis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ghobrial:Amgen: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria; Noxxon: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding.

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7

Higgins, Jack P., Nenad Sarapa, Jason Kim, and Eric Poma. "Unexpected pharmacokinetics of evofosfamide observed in phase III MAESTRO study." Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018): 2568. http://dx.doi.org/10.1200/jco.2018.36.15_suppl.2568.

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8

Pourmorteza, Mohsen, Zia U. Rahman, and Mark Young. "Evofosfamide, a new horizon in the treatment of pancreatic cancer." Anti-Cancer Drugs 27, no. 8 (September 2016): 723–25. http://dx.doi.org/10.1097/cad.0000000000000386.

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9

Spiegelberg, Linda, Stefan J. van Hoof, Rianne Biemans, Natasja G. Lieuwes, Damiënne Marcus, Raymon Niemans, Jan Theys, et al. "Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity." Radiotherapy and Oncology 141 (December 2019): 247–55. http://dx.doi.org/10.1016/j.radonc.2019.06.034.

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10

Anderson, Robert F., Dan Li, and Francis W. Hunter. "Antagonism in effectiveness of evofosfamide and doxorubicin through intermolecular electron transfer." Free Radical Biology and Medicine 113 (December 2017): 564–70. http://dx.doi.org/10.1016/j.freeradbiomed.2017.10.385.

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11

Nytko, Katarzyna J., Ivo Grgic, Sabine Bender, Janosch Ott, Matthias Guckenberger, Oliver Riesterer, and Martin Pruschy. "The hypoxia-activated prodrug evofosfamide in combination with multiple regimens of radiotherapy." Oncotarget 8, no. 14 (February 28, 2017): 23702–12. http://dx.doi.org/10.18632/oncotarget.15784.

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12

Duran, Rafael, Sahar Mirpour, Vasily Pekurovsky, Shanmugasundaram Ganapathy-Kanniappan, Cory F. Brayton, Toby C. Cornish, Boris Gorodetski, et al. "Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer." Clinical Cancer Research 23, no. 2 (July 20, 2016): 536–48. http://dx.doi.org/10.1158/1078-0432.ccr-16-0725.

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13

Kumar, Sushil, Jessica D. Sun, Libo Zhang, Reza Bayat Mokhtari, Bing Wu, Fanying Meng, Qian Liu, et al. "Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models." Translational Oncology 11, no. 4 (August 2018): 911–19. http://dx.doi.org/10.1016/j.tranon.2018.05.004.

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14

Spiegelberg, L., R. Biemans, N. Lieuwes, R. Niemans, J. Theys, A. Yaromina, F. Verhaegen, P. Lambin, and L. Dubois. "PO-1061: Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity." Radiotherapy and Oncology 127 (April 2018): S595. http://dx.doi.org/10.1016/s0167-8140(18)31371-9.

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15

Takakusagi, Yoichi, Shun Kishimoto, Sarwat Naz, Shingo Matsumoto, Keita Saito, Charles P. Hart, James B. Mitchell, and Murali C. Krishna. "Radiotherapy Synergizes with the Hypoxia-Activated Prodrug Evofosfamide: In Vitro and In Vivo Studies." Antioxidants & Redox Signaling 28, no. 2 (January 10, 2018): 131–40. http://dx.doi.org/10.1089/ars.2017.7106.

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16

Hong, Cho Rong, Benjamin D. Dickson, Jagdish K. Jaiswal, Frederik B. Pruijn, Francis W. Hunter, Michael P. Hay, Kevin O. Hicks, and William R. Wilson. "Cellular pharmacology of evofosfamide (TH-302): A critical re-evaluation of its bystander effects." Biochemical Pharmacology 156 (October 2018): 265–80. http://dx.doi.org/10.1016/j.bcp.2018.08.027.

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17

Brenner, Andrew, Richard Zuniga, Jessica D. Sun, John Floyd, Charles P. Hart, Stew Kroll, Lisa Fichtel, et al. "Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study." Neuro-Oncology 20, no. 9 (February 5, 2018): 1231–39. http://dx.doi.org/10.1093/neuonc/noy015.

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18

McWhirter, Elaine, Omid Hamid, Bartosz Chmielowski, Richard D. Carvajal, David A. Jaffray, Brandon Driscoll, Tina Shek, et al. "A Phase 2 biomarker-enriched study of evofosfamide (TH-302) in patients with advanced melanoma." Journal of Clinical Oncology 33, no. 15_suppl (May 20, 2015): TPS9089. http://dx.doi.org/10.1200/jco.2015.33.15_suppl.tps9089.

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19

Badar, Talha, Damian R. Handisides, Juliana M. Benito, Mary Ann Richie, Gautam Borthakur, Elias Jabbour, Karine Harutyunyan, et al. "Phase I study of evofosfamide, an investigational hypoxia-activated prodrug, in patients with advanced leukemia." American Journal of Hematology 91, no. 8 (June 25, 2016): 800–805. http://dx.doi.org/10.1002/ajh.24415.

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20

Jardim-Perassi, Bruna V., Wei Mu, Suning Huang, Michal R. Tomaszewski, Jan Poleszczuk, Mahmoud A. Abdalah, Mikalai M. Budzevich, et al. "Deep-learning and MR images to target hypoxic habitats with evofosfamide in preclinical models of sarcoma." Theranostics 11, no. 11 (2021): 5313–29. http://dx.doi.org/10.7150/thno.56595.

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Hunter, Francis W., Jules B. L. Devaux, Fanying Meng, Cho Rong Hong, Aziza Khan, Peter Tsai, Troy W. Ketela, et al. "Functional CRISPR and shRNA Screens Identify Involvement of Mitochondrial Electron Transport in the Activation of Evofosfamide." Molecular Pharmacology 95, no. 6 (April 12, 2019): 638–51. http://dx.doi.org/10.1124/mol.118.115196.

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22

Liapis, Vasilios, Irene Zinonos, Agatha Labrinidis, Shelley Hay, Vladimir Ponomarev, Vasilios Panagopoulos, Aneta Zysk, et al. "Anticancer efficacy of the hypoxia‐activated prodrug evofosfamide (TH‐302) in osteolytic breast cancer murine models." Cancer Medicine 5, no. 3 (January 9, 2016): 534–45. http://dx.doi.org/10.1002/cam4.599.

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23

Zhang, Libo, Paula Marrano, Bing Wu, Sushil Kumar, Paul Thorner, and Sylvain Baruchel. "Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models." Clinical Cancer Research 22, no. 11 (December 30, 2015): 2697–708. http://dx.doi.org/10.1158/1078-0432.ccr-15-1853.

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24

Huang, Yan, Ying Tian, Yuanyuan Zhao, Cong Xue, Jianhua Zhan, Lin Liu, Xiaobo He, and Li Zhang. "Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo." Cancer Communications 38, no. 1 (May 3, 2018): 15. http://dx.doi.org/10.1186/s40880-018-0285-0.

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25

Sun, Jessica D., Qian Liu, Dharmendra Ahluwalia, Damien J. Ferraro, Yan Wang, Don Jung, Mark D. Matteucci, and Charles P. Hart. "Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models." Cancer Biology & Therapy 17, no. 4 (January 28, 2016): 371–80. http://dx.doi.org/10.1080/15384047.2016.1139268.

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26

Younger, Eugenie, Zsuzsanna Papai, Brian Andrew Van Tine, Steven Attia, Karla V. Ballman, Yao Lu, Denise K. Reinke, Patrick Schoffski, William D. Tap, and Robin Lewis Jones. "Subgroup analysis of elderly patients treated within the randomized phase 3 doxorubicin versus doxorubicin plus evofosfamide (SARC021) trial." Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018): 11575. http://dx.doi.org/10.1200/jco.2018.36.15_suppl.11575.

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Domenyuk, Valeriy, Daniel Magee, Zoran Gatalica, Adam Stark, Patrick Kennedy, Anna Barker, Donald A. Berry, et al. "Poly-ligand profiling (PLP) to differentiate pancreatic cancer patients who benefit from gemcitabine+evofosfamide versus gemcitabine+placebo treatment." Journal of Clinical Oncology 36, no. 15_suppl (May 20, 2018): 12067. http://dx.doi.org/10.1200/jco.2018.36.15_suppl.12067.

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Yoon, J. S., K. H. Lee, G. J. Cheon, Y. J. Bang, and D. Y. Oh. "Phase II study of evofosfamide (TH-302) monotherapy as a second-line treatment in advanced biliary tract cancer." Annals of Oncology 29 (October 2018): viii259. http://dx.doi.org/10.1093/annonc/mdy282.142.

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Younger, Eugenie, Karla Ballman, Yao Lu, Zsuzsanna Pápai, Brian A. Van Tine, Steven Attia, Patrick Schöffski, Denise Reinke, William D. Tap, and Robin L. Jones. "Subgroup analysis of older patients treated within the randomized phase 3 doxorubicin versus doxorubicin plus evofosfamide (SARC021) trial." Journal of Geriatric Oncology 11, no. 3 (April 2020): 463–69. http://dx.doi.org/10.1016/j.jgo.2019.05.008.

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Liapis, Vasilios, Aneta Zysk, Mark DeNichilo, Irene Zinonos, Shelley Hay, Vasilios Panagopoulos, Alexandra Shoubridge, et al. "Anticancer efficacy of the hypoxia-activated prodrug evofosfamide is enhanced in combination with proapoptotic receptor agonists against osteosarcoma." Cancer Medicine 6, no. 9 (August 10, 2017): 2164–76. http://dx.doi.org/10.1002/cam4.1115.

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31

Tran, Nguyen H., Nathan R. Foster, Amit Mahipal, Thomas Byrne, Joleen Hubbard, Alvin Silva, Kabir Mody, Steven Alberts, and Mitesh J. Borad. "Phase IB study of sorafenib and evofosfamide in patients with advanced hepatocellular and renal cell carcinomas (NCCTG N1135, Alliance)." Investigational New Drugs 39, no. 4 (March 1, 2021): 1072–80. http://dx.doi.org/10.1007/s10637-021-01090-w.

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32

Lüpfert, Christian, Martin Dyroff, Oliver von Richter, Dieter Gallemann, Samer El Bawab, Hugues Dolgos, Don Jung, Stefan Hecht, and Andreas Johne. "A Novel PBPK Modeling Approach to Assess Cytochrome P450 Mediated Drug-Drug Interaction Potential of the Cytotoxic Prodrug Evofosfamide." CPT: Pharmacometrics & Systems Pharmacology 7, no. 12 (October 31, 2018): 829–37. http://dx.doi.org/10.1002/psp4.12360.

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Zhang, Shengchi, Li Li, Xianfeng Wei, Xiang Mao, Xueqing Zhang, Yao Liu, Mei Wei, Wei Wang, and Lun Zhang. "Targeting Mesoporous Silica for Synergistic TH-302 and Afatinib Delivery to Nasopharyngeal Carcinoma." Nanoscience and Nanotechnology Letters 12, no. 9 (September 1, 2020): 1127–36. http://dx.doi.org/10.1166/nnl.2020.3211.

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Tumor hypoxia is considered as an important factor for tumor metastasis and disease recurrence. Evofosfamide (TH-302) is a hypoxic prodrug, which can selectively target the hypoxic area of solid tumors, and has the potential to improve the efficacy of the commercial anticancer drug afatinib (AFT). However, free hydrophobic AFT and hydrophilic TH-302 still have several unequivocal deficiencies, such as unsatisfactory tumor inhibition rate, serious side effects and being easy to induce multidrug resistance. Moreover, the operation process of co-administration is too complicated. Therefore, this paper discussed the synergistic effects of AFT/TH-302 and developed a kind of co-loaded targeted mesoporous silica nanoparticles (MSNs) for the treatment of nasopharyngeal carcinoma (NPC). The calculated proportion of AFT and TH-302 were encapsulated by folic acid (FA) modified MSNs (FA-MSNs). In vitro experiments showed that free AFT and TH-302 had synergistic effect, while MSNs nanocarrier could significantly reduce the half maximal inhibitory concentrations (IC50) of AFT and TH-302. AFT and TH-302 show significant synergistic on NPC cells, the application of MSN carrier platform including fixed proportion of AFT and TH-302 improves the synergistic effect and provides a new idea for the treatment of NPC.

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Xu, Yinyin, Jing Guo, Jing Liu, Ying Xie, Xin Li, Hongmei Jiang, Jingjing Wang, et al. "Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma." Oncogene 40, no. 7 (January 8, 2021): 1231–41. http://dx.doi.org/10.1038/s41388-020-01590-8.

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AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

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Hajj, Carla, James Russell, Charles P. Hart, Karyn A. Goodman, Maeve A. Lowery, Adriana Haimovitz-Friedman, Joseph O. Deasy, and John L. Humm. "A Combination of Radiation and the Hypoxia-Activated Prodrug Evofosfamide (TH-302) is Efficacious against a Human Orthotopic Pancreatic Tumor Model." Translational Oncology 10, no. 5 (October 2017): 760–65. http://dx.doi.org/10.1016/j.tranon.2017.06.010.

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36

Domenyuk, V., X. Liu, D. Magee, Z. Gatalica, A. Stark, P. Kennedy, M. Rosenow, et al. "Poly-Ligand Profiling differentiates pancreatic cancer patients according to treatment benefit from gemcitabine+placebo versus gemcitabine+evofosfamide and identifies candidate targets." Annals of Oncology 29 (June 2018): v36. http://dx.doi.org/10.1093/annonc/mdy151.131.

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37

Hegde, Aparna, Priyamvada Jayaprakash, Coline A. Couillault, Sarina Piha-Paul, Daniel Karp, Jordi Rodon, Shubham Pant, et al. "A Phase I Dose-Escalation Study to Evaluate the Safety and Tolerability of Evofosfamide in Combination with Ipilimumab in Advanced Solid Malignancies." Clinical Cancer Research 27, no. 11 (March 26, 2021): 3050–60. http://dx.doi.org/10.1158/1078-0432.ccr-20-4118.

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Laubach, Jacob P., Chia-Jen Liu, Noopur S. Raje, Andrew J. Yee, Philippe Armand, Robert L. Schlossman, Jacalyn Rosenblatt, et al. "A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma." Clinical Cancer Research 25, no. 2 (October 2, 2018): 478–86. http://dx.doi.org/10.1158/1078-0432.ccr-18-1325.

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39

Hong, Cho Rong, William R. Wilson, and Kevin O. Hicks. "An Intratumor Pharmacokinetic/Pharmacodynamic Model for the Hypoxia-Activated Prodrug Evofosfamide (TH-302): Monotherapy Activity is Not Dependent on a Bystander Effect." Neoplasia 21, no. 2 (February 2019): 159–71. http://dx.doi.org/10.1016/j.neo.2018.11.009.

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López-López, Carlos, Teresa Alonso Gordoa, Marta Benavent, Jaume Capdevila, Alex Teule, Ana Custodio, Isabel Sevilla, et al. "Molecular correlation of the activity of evofosfamide (EVO) in combination with sunitinib (SUN) in pancreatic Neuroendocrine Tumors (pNETs) in the SUNEVO GETNE Trial." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16706-e16706. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16706.

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e16706 Background: MEN1, DAXX, ATRX, and PI3K/AKT/mTOR pathway genes are frequently mutated in pNETs. Sunitinib is approved and widely used in the metastatic setting but unfortunately, no validated predictive biomarker has been identified to guide therapy yet. The SUNEVO phase II trial of the Spanish Task Force Group for Neuroendocrine and Endocrine Tumours (GETNE) trial combined the pro-drug of EVO under SUN-induced hypoxic conditions. Methods: We performed an exploratory analysis aimed to identify somatic mutations associated with the clinical benefit of pNET patients treated with SUN+EVO combination. Seventeen treatment-naïve pts with pNETS were included in the SUNEVO trial, and 4 (23.5%) achieved a partial response (by RECIST 1.1). Tumor DNA from 10 FFPE tumor samples were successfully sequenced with an enrichment panel (Nimblegen, Roche) including 42 cancer-related genes and TERT promoter region. Median coverage was 793x. Coding non-synonymous and loss-of-function variants were considered for the analysis. Final analysis included tumor samples from the 10 patients with NGS results. Results: Somatic mutations were found in MEN1 (70%), DAXX (30%), ATRX (20%), SETD2 (20%) and PTEN (10%). Mutations in the telomere maintenance genes DAXX and ATRX were concordant with mutual exclusivity. The loss of MEN1 was associated with a greater number of mutations (p = 0.019). Patients with complete and partial response showed heterogeneous genetic profiles. Conclusions: The molecular alterations of the patients in the SUNEVO trial were consistent with those previously described for metastatic pNETs. No clear association between molecular defects and treatment response was found. Clinical trial information: NCT02402062 .

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41

Goldman, J., C. Belani, S. Novello, J. von Pawel, T. Csoszi, S. Orlov, S. Kroll, and T. Pearce. "Randomized, Double-Blind, Placebo-Controlled Trial of Evofosfamide (TH-302) in Combination with Pemetrexed in Advanced Non-Squamous Non-Small Cell Lung Cancer." Annals of Oncology 26 (April 2015): i29. http://dx.doi.org/10.1093/annonc/mdv050.46.

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Borad, Mitesh J., Eunice Lee Kwak, Andrea Wang-Gillam, Ayman Ibrahim, Julie Aldridge, and Anthony J. Olszanski. "Evofosfamide combined with gemcitabine/nab-paclitaxel in patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma (PAC): Results of a phase I trial." Journal of Clinical Oncology 34, no. 15_suppl (May 20, 2016): 4114. http://dx.doi.org/10.1200/jco.2016.34.15_suppl.4114.

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43

Csõszi, Tibor, Jonathan Wade Goldman, Maria Szilasi, Joachim Von Pawel, Silvia Novello, Corey Allan Carter, Tudor-Eliade Ciuleanu, et al. "Randomized, double-blind, placebo-controlled trial of evofosfamide (Evo) and pemetrexed (Pem) in advanced non-squamous non-small cell lung cancer (n-s NSCLC)." Journal of Clinical Oncology 34, no. 15_suppl (May 20, 2016): 9075. http://dx.doi.org/10.1200/jco.2016.34.15_suppl.9075.

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44

Borad, M., L. Renfro, N. Foster, P. Martin, S. Alberts, J. Hubbard, A. Silva, T. Halfdanarson, T. Byrne, and C. Erlichman. "P-100 Phase IB study of sorafenib + evofosfamide in patients (pts) with advanced hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC): NCCTG N1153 (Alliance)." Annals of Oncology 27 (June 2016): ii29. http://dx.doi.org/10.1093/annonc/mdw199.95.

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45

Haynes, Jennifer, Trevor D. McKee, Andrew Haller, Yadong Wang, Cherry Leung, Deena M. A. Gendoo, Evelyne Lima-Fernandes, et al. "Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer." Clinical Cancer Research 24, no. 9 (February 23, 2018): 2116–27. http://dx.doi.org/10.1158/1078-0432.ccr-17-1715.

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46

Liu, Arthur, and Michael Curran. "730 Hypoxia reduction in tandem with anti-angiogenic therapy remodels the PDAC microenvironment and potentiates CD40 agonist therapy." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A759. http://dx.doi.org/10.1136/jitc-2021-sitc2021.730.

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BackgroundThe majority of patients with pancreatic ductal adenocarcinoma (PDAC) fail to derive any durable responses from single agent immune checkpoint blockade therapy. This refractory state originates from PDAC's unique tumor microenvironment that is densely populated by immunosuppressive myeloid cells while excluding most antitumor CD8 T cells.1 In addition, PDAC is highly hypoxic and exhibits poor vascularity, both qualities which further limit antitumor immunity.2 3 We showed that the hypoxia-activated prodrug TH-302 (Evofosfamide) potentiates immunotherapy responses.4 Mechanistically, TH-302 decreases intratumoral hypoxia and initiates normalization of the tumor vasculature. While TH-302 facilitates a cellular remodeling process that diminishes tumor hypoxia, the nature of the vascular remodeling involved remains unknown, as do the downstream consequences for the composition of the tumor microenvironment and responsiveness to immunotherapy. We hypothesized that anti-angiogenic therapy and Evofosfamide might cooperate to normalize tumor vasculature and diminish hypoxia.MethodsTH-302 and a vascular endothelial growth factor receptor-2 (VEGFR-2) blocking antibody were used to treat several syngeneic murine models, including orthotopic pancreatic cancer and a transplantable model of prostate cancer. Immunofluorescence and flow cytometry were used to assess intratumoral hypoxia, vessel normalization, and tumor immune infiltrate.ResultsWe find that anti-VEGFR-2 (DC101) in combination with TH-302 demonstrates a cooperative benefit to combat both orthotopically implanted pancreatic cancer and transplantable prostate cancer. Combination therapy reduces intratumoral hypoxia, leads to pruning of the tumor vasculature, and increases the infiltration of endothelial cells into hypoxic regions. Across models, the combination of DC101 and TH-302 significantly enhance CD8 T cell function and limits their exhausted state. At the same time, tumor associated macrophages exhibit decreased expression of M2-like features. Similar to other anti-angiogenic therapies, combination DC101 and TH-302 leads to an increased frequency of PD-L1 expressing cells. Concurrent anti-PD-1 failed to provide any additional therapeutic benefit, which in part may be due poor CD8 T cell infiltration. Instead, we find that CD40 agonist therapy is improved when combined with TH-302 and DC101.ConclusionsTH-302 and DC101 utilize unique yet complementary mechanisms to improve the survival of mice challenged with pancreatic or prostate tumors. This combination relieves hypoxia and simultaneously reinvigorates T cell function and reduces macrophage mediated immunosuppression. In this setting, CD40 agonist therapy provides an additive benefit in prolonging mouse survival. Put together, these data indicate that targeted hypoxia reduction with anti-angiogenic therapy remodels the tumor microenvironment and enhances immunotherapy responses in PDAC.ReferencesBear AS, Vonderheide RH, O'Hara MH. Challenges and opportunities for pancreatic cancer immunotherapy. Cancer Cell. 2020;38(6):788–802. doi: 10.1016/j.ccell.2020.08.004. Epub 2020 Sep 17. PMID: 32946773; PMCID: PMC7738380.Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, Bastidas AJ, Vierra M. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 2000;48(4):919–22. doi: 10.1016/s0360-3016(00)00803-8. PMID: 11072146.Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324(5933):1457–61. doi: 10.1126/science.1171362. Epub 2009 May 21. PMID: 19460966; PMCID: PMC2998180.Jayaprakash P, Ai M, Liu A, Budhani P, Bartkowiak T, Sheng J, Ager C, Nicholas C, Jaiswal AR, Sun Y, Shah K, Balasubramanyam S, Li N, Wang G, Ning J, Zal A, Zal T, Curran MA. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J Clin Invest 2018;128(11):5137–5149. doi: 10.1172/JCI96268. Epub 2018 Oct 15. PMID: 30188869; PMCID: PMC6205399.

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47

Leblond, Pierre, Pauline Navarin, Mélanie Arcicasa, Christine Bal-Mahieu, Nicole Lemahieu, Pamela Völkel, Eric Lartigau, Pierre-Olivier Angrand, and Samuel Meignan. "PCM-13THE HYPOXIA-ACTIVATED PRODRUG EVOFOSFAMIDE (TH-302) IS EFFICACIOUS IN PEDIATRIC HIGH GRADE GLIOMA CELL LINES AS A MONOTHERAPY AND IN COMBINATION WITH CHEMOTHERAPIES." Neuro-Oncology 18, suppl 3 (June 2016): iii141.5—iii142. http://dx.doi.org/10.1093/neuonc/now080.13.

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48

Tomaszewski, Michal R., Shuxuan Fan, Alberto Garcia, Jin Qi, Youngchul Kim, Robert A. Gatenby, Matthew B. Schabath, et al. "AI-Radiomics Can Improve Inclusion Criteria and Clinical Trial Performance." Tomography 8, no. 1 (February 2, 2022): 341–55. http://dx.doi.org/10.3390/tomography8010028.

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Purpose: Success of clinical trials increasingly relies on effective selection of the target patient populations. We hypothesize that computational analysis of pre-accrual imaging data can be used for patient enrichment to better identify patients who can potentially benefit from investigational agents. Methods: This was tested retrospectively in soft-tissue sarcoma (STS) patients accrued into a randomized clinical trial (SARC021) that evaluated the efficacy of evofosfamide (Evo), a hypoxia activated prodrug, in combination with doxorubicin (Dox). Notably, SARC021 failed to meet its overall survival (OS) objective. We tested whether a radiomic biomarker-driven inclusion/exclusion criterion could have been used to improve the difference between the two arms (Evo + Dox vs. Dox) of the study. 164 radiomics features were extracted from 296 SARC021 patients with lung metastases, divided into training and test sets. Results: A single radiomics feature, Short Run Emphasis (SRE), was representative of a group of correlated features that were the most informative. The SRE feature value was combined into a model along with histological classification and smoking history. This model as able to identify an enriched subset (52%) of patients who had a significantly longer OS in Evo + Dox vs. Dox groups [p = 0.036, Hazard Ratio (HR) = 0.64 (0.42–0.97)]. Applying the same model and threshold value in an independent test set confirmed the significant survival difference [p = 0.016, HR = 0.42 (0.20–0.85)]. Notably, this model was best at identifying exclusion criteria for patients most likely to benefit from doxorubicin alone. Conclusions: The study presents a first of its kind clinical-radiomic approach for patient enrichment in clinical trials. We show that, had an appropriate model been used for selective patient inclusion, SARC021 trial could have met its primary survival objective for patients with metastatic STS.

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Sattiraju, Anirudh, Valerie Marallano, Roland Friedel, and Hongyan Zou. "TMIC-59. INVESTIGATING PHYSIOLOGY OF THERAPY RESISTANT, TUMOR-INITIATING GBM CELLS IN HYPOXIC NICHES USING SPATIALLY-SENSITIVE HYPOXIA REPORTER SYSTEM AND SINGLE-CELL RNA SEQUENCING." Neuro-Oncology 21, Supplement_6 (November 2019): vi260—vi261. http://dx.doi.org/10.1093/neuonc/noz175.1093.

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Abstract Glioblastoma (GBM) is the most common and lethal brain cancer that invariably recurs after therapy due to presence of resistant GBM cells within hypoxic and peri-necrotic regions. Eradicating such GBM cells, which constitute a major source of tumor recurrence, is important to curb disease relapse. An endogenously expressed, spatially sensitive hypoxia reporter would therefore be a valuable tool to evaluate hypoxic zones in GBM in detail, and to measure the efficacy of hypoxia-activated drugs. For this purpose, we engineered a lentiviral vector that carries a hypoxia reporter, consisting of HIF response elements (HRE) that drive expression of UnaG fluorescent protein, which fluoresces independent of oxidative maturation. We validated the sensitivity of our reporter in vitro using U87MG, GBM2, and patient-derived GBM stem cell lines, and we performed intracranial transplantations of GBM cells in SCID mice to identify cells undergoing hypoxic stress in in vivo microenvironment. In addition, GL261 murine GBM cells with hypoxia reporter were intracranially implanted in C57BL/6 mice as syngeneic model for studies on immune responses. Brains from our transplant studies were dissociated and single-cell RNA sequencing (Drop-Seq) was performed to investigate heterogeneity in response to hypoxia within GBM cells and the cellular composition of microenvironment. We will also apply a hypoxia-activated prodrug, Evofosfamide (Evo), in our ongoing studies that can potentially eradicate hypoxic tumor cells and increase T cell infiltration and reverse immune suppression. As hypoxic niches are thought to confer resistance to radiation therapy (XRT), combining XRT with Evo could thus improve therapy efficacy. Our hypoxia gene reporter, combined with single-cell transcriptomics, could therefore serve as an effective tool to enable fundamental investigation of GBM microenvironment and could be used to evaluate therapies targeting tumor microenvironment to enhance GBM patient survival.

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Hajj, C., J. Russel, A. Haimovitz-Friedman, K. A. Goodman, and J. Humm. "Metabolism of Hypoxia-Activated Prodrug Evofosfamide in Hypoxic and Normoxic Conditions and Its Potential to Enhance the Therapeutic Efficacy of Single-Dose Radiation Therapy in Pancreatic Cancer." International Journal of Radiation Oncology*Biology*Physics 93, no. 3 (November 2015): S184. http://dx.doi.org/10.1016/j.ijrobp.2015.07.440.

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