Two Case Reports of Resensitization to Previous Chemotherapy with the Novel Hypoxia-Activated Hypomethylating Anticancer Agent RRx-001 in Metastatic Colorectal Cancer Patients

Abstract

The development of chemoresistance is a persistent problem during the treatment of cancer. Although reversion or modification of acquired chemoresistance has been previously observed, no systematic exploration has been undertaken. Here, we report a case study of 2 male patients, 62 and 66 years old, both with histologically proven, radiologically progressing, extensively pretreated, metastatic and refractory (≥2 conventional regimens and drug therapy) colorectal adenocarcinoma that was previously treated with FOLFIRI. The patients were resensitized to FOLFIRI after exposure to RRx-001 in the context of a phase-1 study. RRx-001 is a novel, hypomethylating and free-radical-inducing anticancer agent that activates nitrite reduction to NO under hypoxia and has an impact on epigenetic pathways. The repression of DNA methyltransferase 1 by RRx-001 may lead to demethylation and reexpression of silenced tumor suppressor genes, leading to resensitization. These examples provide insight into a nascent strategy to improve the prognosis in heavily pretreated cancer patients and suggest routes for further exploration.

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials

“…Following RRx-001 administration, four subjects were successfully rechallenged with previously effective but now refractory therapies, indicative of resensitization. The median overall survival was approximately 18 months (median follow-up time was approximately 13 months) in these four patients, counting from the first dose of RRx-001 administration ( Figure 2) [4,15,17].…”

“…Secondarily, because mechanisms of chemoresistance are multifactorial, epigenetic modulation and inhibition of drug efflux transporters also seem to be involved []. Phase I [17] and Phase II [32] clinical trials have demonstrated that RRx-001 sensitizes tumors to different chemotherapeutic agents including irinotecan, cisplatin/carboplatin, docetaxel, paclitaxel, nab-paclitaxel, etoposide, bevacizumab, and 5-FU. Chemosensitization also has been observed preclinically in cancers of the brain and in multiple myeloma [31], while immunosensitization (potentiation of checkpoint inhibitor activity) has occurred in a myeloma J558L model [].…”

Gasotransmitters in cancer: from pathophysiology to experimental therapy

“…RRx-001, a novel, hypomethylating and free-radical-inducing anticancer agent that activates nitrite reduction to NO under hypoxia, is currently in Phase I trials. 213 In addition to pharmacological NO donation, upregulation of inducible NOS (iNOS) in tumour-associated macrophages may also confer radiosensitization. 214 The clinical translation of this approach may be possible, for instance by using ONO-4007 (a non-specific immunostimulant synthetic lipid A analogue) that was designed as a pharmacological upregulator of iNOS expression, and a compound with established antitumor effects in preclinical models, which has already completed Phase I clinical trials.…”

Episensitization: Therapeutic Tumor Resensitization by Epigenetic Agents: A Review and Reassessment

“…RRx-001- enhanced susceptibility to chemotherapy was observed in at least 5 patients, 4 with colorectal cancer and 1 with NSCLC, with drugs to which the patients were previously resistant. A case report was recently published describing the resensitization of two colorectal cancer patients to FOLFIRI, which both patients had previously failed [ 23 ]. RRx-001 has multiple mechanisms of action, including induction of redox and metabolic stress on the tumor, which can disrupt multiple cellular pathways via sulfhydryl oxidation, Nrf2 activation and p53 upregulation, PARP cleavage, HIF-1 alpha and inhibition of G6PD, a central substrate of the Pentose Phosphate Pathway (RadioRx, unpublished data).…”