Abstract 4959: CP-506, a next generation hypoxia-activated prodrug, as promising novel anti-cancer therapeutic

Abstract

Hypoxia is a characteristic of many solid tumors and is defined as a low level or absence of oxygen due to an insufficient vascularization of the tumor or a transient blockage of blood vessels. Hypoxia activates a survival response within the tumor cells driving cancer progression and is associated with poor prognosis. Hypoxia-activated prodrugs (HAPs) are anti-neoplastic agents that can solely be activated in hypoxic areas allowing the targeted delivery of cytotoxic compounds in the hypoxic tumor niches. Convert Pharmaceuticals is developing CP-506, a novel generation of HAP presenting a strong bystander effect. A key step in the activation of CP-506 is its conversion by one-electron reductases to an oxygen-sensing intermediate. Under normoxic conditions, the intermediate is rapidly re-oxidized to the pro-drug. However, under severe hypoxic conditions, further reduction steps lead to the generation of the active cytotoxic metabolite, CP-506M. In an in vitro cytotoxicity assay, CP-506 significantly inhibited the viability of several tumor cell lines specifically under anoxic conditions. In spheroid models, CP-506 demonstrates a strong bystander effect i.e. the ability of the active metabolite to locally diffuse beyond the hypoxic core and induce tumor cell death. CP-506 was administered intraperitoneally at a dose of 600 mg/kg once a day for 5 consecutive days and showed a significant inhibition of tumor growth in four tumor xenograft models (triple negative breast cancer, lung and pancreatic cancers). In all tumor models, CP-506 treatment significantly increased the survival of treated mice assessed by the time to reach four times the start volume as a surrogate endpoint for survival. Different dosing regimens for CP-506 were investigated and all demonstrated a significant tumor growth inhibition compared to the vehicle group. The most profound anti-tumor effect was observed for the repeated cycles of daily consecutive administrations. Finally, no cumulative toxicity was observed for any of the repeated dosing schedules as indicated by bodyweight change. The successful development of CP-506 will require combination with treatments targeting well-oxygenated cells and the careful selection of patients predicted to benefit from a HAP treatment. To this end, we are currently identifying key parameters (presence of tumor hypoxia, expression of reductases and DNA repair capacity) in the activation of CP-506 to define predictive gene signatures in liquid biopsies enabling patient selection. Our current pre-clinical data strongly suggest that CP-506 is a potent, highly selective HAP with a favorable pharmacokinetic profile and the addition of predictive gene signatures or imaging biomarkers for patient selection holds great promise for the treatment of cancer. Citation Format: sophie thiolloy, Sofie Deschoemaeker, Nicolas Ongenae, Julie Gilissen, Ludwig Dubois, Ala Yaromina, Amir Ashoorzadeh, Jeff Smaill, Adam Patterson, Philippe Lambin, Arne Heyerick. CP-506, a next generation hypoxia-activated prodrug, as promising novel anti-cancer therapeutic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4959.

Interfering with Tumor Hypoxia for Radiotherapy Optimization

“…Nitrogen mustard-DNA crosslinking-based PR-104 is another novel hypoxia-activated prodrug that failed to fulfill the expectations derived from preclinical data; dose-limiting hematological toxicities prevented the advancement of the drug beyond phase I/II clinical trials [ 196 , 206 – 209 ]. Novel nitrobenzamides based on PR-104 are being developed with CP-506 showing interesting results on the preclinical level [ 210 ]. One of the major questions to be resolved is the relevance of scheduling of the combined treatment modality of hypoxia-activated prodrugs in combination with high-dose radiotherapy [ 203 ].…”

The Role of Metabolism in Tumor Immune Evasion: Novel Approaches to Improve Immunotherapy

“…In the preclinical setting, some drugs are being evaluated: IDF-11774 [ 168 ] and RX-0047 [ 169 ] that are HIF-1α inhibitors and CP-506 [ 170 ], a hypoxia-activated prodrug.…”