title: 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.
authors.affiliation: Moores Cancer Center, UCSD, La Jolla, Calif., USA.
authors.forename: T
authors.initials: T
authors.lastname: Reid
authors.affiliation: Moores Cancer Center, UCSD, La Jolla, Calif., USA.
authors.forename: S
authors.initials: S
authors.lastname: Dad
authors.affiliation: Imaging Endpoints, Scottsdale, Ariz., USA.
authors.forename: R
authors.initials: R
authors.lastname: Korn
authors.affiliation: RadioRx, Inc., Mountain View, Calif., USA.
authors.forename: B
authors.initials: B
authors.lastname: Oronsky
authors.affiliation: Stanford University Medical Center, Stanford, Calif., USA.
authors.forename: S
authors.initials: S
authors.lastname: Knox
authors.affiliation: RadioRx, Inc., Mountain View, Calif., USA.
authors.forename: J
authors.initials: J
authors.lastname: Scicinski
keywords: Epigenetic resensitization; Hypoxia activation; Oxidation