title: RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials.
abstract: According to Hanahan and Weinberg, cancer manifests as six essential physiologic hallmarks: (1) self-sufficiency in growth signals, (2) insensitivity to growth-inhibitory signals, (3) evasion of programmed cell death, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) invasion and metastasis. As a facilitator of these traits as well as immunosuppression and chemoresistance, the presence of tumor-associated macrophages (TAMs) may serve as the seventh hallmark of cancer. Anticancer agents that successfully reprogram TAMs to target rather than support tumor cells may hold the key to better therapeutic outcomes. Areas covered: This article summarizes the characteristics of the macrophage-stimulating agent RRx-001, a molecular iconoclast, sourced from the aerospace industry, with a particular emphasis on the cell-to-cell transfer mechanism of action (RBCs to TAMs) underlying its antitumor activity as well as its chemo and radioprotective properties, consolidated from various preclinical and clinical studies. Expert opinion: RRx-001 is macrophage-stimulating agent with the potential to synergize with chemotherapy, radiotherapy and immunotherapy while simultaneously protecting normal tissues from their cytotoxic effects. Given the promising indications of activity in multiple tumor types and these normal tissue protective properties, RRx-001 may be used to treat a broad spectrum of malignancies, if it is approved in the future.
authors.affiliation: a EpicentRx (no department).
authors.forename: Bryan
authors.initials: B
authors.lastname: Oronsky
authors.affiliation: b Department of Radiology , Stanford University , Palo Alto , CA , USA.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Paulmurugan
authors.affiliation: b Department of Radiology , Stanford University , Palo Alto , CA , USA.
authors.forename: Kira
authors.initials: K
authors.lastname: Foygel
authors.affiliation: a EpicentRx (no department).
authors.forename: Jan
authors.initials: J
authors.lastname: Scicinski
authors.affiliation: c Department of Radiation Oncology , Stanford University , Palo Alto , CA , USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Knox
authors.affiliation: d Department of Urology , Stanford University , Palo Alto , CA , USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Peehl
authors.affiliation: d Department of Urology , Stanford University , Palo Alto , CA , USA.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: c Department of Radiation Oncology , Stanford University , Palo Alto , CA , USA.
authors.forename: Shoucheng
authors.initials: S
authors.lastname: Ning
authors.affiliation: f Department of Bioengineering , University of California at San Diego (UCSD ) , La Jolla , CA , USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
authors.affiliation: g Murtha Cancer Center , Walter Reed National Military Medical Center ; Bethesda , MD , USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Summers
authors.affiliation: h Moores Cancer Center , University of California at San Diego (UCSD) , CA , USA.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Reid
authors.affiliation: e Department of Anesthesia , Stanford University , Palo Alto , CA , USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Fitch
authors.affiliation: k Innovexe.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Kim
authors.affiliation: i National Cancer Institute , National Institutes of Health , Bethesda , MD , USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: i National Cancer Institute , National Institutes of Health , Bethesda , MD , USA.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: j John Wayne Cancer Institute, Providence Saint John's Health Center , CA , USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.affiliation: k Innovexe.
authors.forename: Nacer D
authors.initials: ND
authors.lastname: Abrouk
authors.affiliation: l Department of pharmacology , Uniformed Services University , Bethesda , MD , USA.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Day
authors.affiliation: m InterWest Partners.
authors.forename: Arnold
authors.initials: A
authors.lastname: Oronsky
authors.affiliation: n Cancer Center, St. Francis Hospital , Hartford , CT , USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Ray
authors.affiliation: g Murtha Cancer Center , Walter Reed National Military Medical Center ; Bethesda , MD , USA.
authors.forename: Corey A
authors.initials: CA
authors.lastname: Carter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001384:Azetidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009574:Nitro Compounds / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D009574:Nitro Compounds; C577469:RRx-001
keywords: RRx-001; Tumor associated macrophages; cancer stem cells; cancer therapy