Abstract 2981: Targeting solid tumor acidic microenvironment with an alphalex PARP inhibitor

Abstract

Poly (ADPribose) polymerase inhibitors (PARPi) have shown great promise in the treatment of cancer, however, their current clinical use has been largely limited to homologous recombination-deficient (HRD) tumors. While these drugs are efficacious as monotherapies, durable responses beyond 12 months are uncommon and their activity against HRD-negative tumors is limited. These findings have prompted great interest in combining PARPi’s with chemotherapy to increase the duration of response in HRD-positive tumors and expand the activity of these drugs against HRD-negative tumors which comprise a much greater fraction of the total number of cancer cases each year. While such combinations are highly active against tumors independent of HRD status, they are also extremely cytotoxic against bone marrow cells. As such, dose reductions ranging from 5- to 20-fold are required when PARPi’s are combined with chemotherapy which has resulted in favorable safety profiles but limited efficacy. Tumor-targeting strategies could overcome this efficacy barrier but the technologies developed thus far are limited by numerous issues, including: (a) lack of universal, non-saturating tumor-targeting mechanisms which limit their use to specific tumor types and their corresponding antigens, (b) inability to deliver therapeutically relevant levels of drug(s) directly into tumor cells, and (c) insufficient tumor penetration leading to sub-optimal tumor exposure. Herein, we report the development of alphalex, a novel tumor-targeted drug delivery platform which allows the efficient and selective delivery of PARPi’s into tumors with significant normal-tissue sparing. Tumor-targeting is achieved using a pH- sensitive peptide which forms an alpha-helix in cellular membrane under low pH conditions associated with the tumor microenvironment. Under these conditions, the peptide translocates across cancer cell membranes to deliver the PARPi directly into the cytoplasm. We demonstrate that alphalex peptide-based conjugates can be combined safely and effectively with both cytotoxic chemotherapies and radiation therapy (RT) and that this approach can be used to selectively kill both HRD-positive and –negative tumors with significant sparing of the bone marrow. The safety and efficacy of the approach was demonstrated in both engineered and patient-derived xenografts (PDXs) in vivo using two FDA-approved PARPi’s across two independent laboratories. These data highlight an entirely new approach to apply PARPi’s against solid tumors independent of HRD status. Furthermore, our approach can be applied to a diverse range of DNA repair inhibitors for potent and selective chemo/radio-sensitization in a tissue-agnostic manner. Citation Format: Vishwas Paralkar, Robert J. Aiello, Dan Marshall, Johanna Csengery, Patricia Bourassa, Qing Zhang, Brett S. Robinson, Lori Lopresti-Morrow, Jane Bechtold, Laurie Tylaska, Timothy Paradis, Gregory Slaybaugh, Hanna Visca, Anna Moshnikova, Dhammika Weerakkody, Oleg Andreev, Yana K. Reshetnyak, Donald Engelman, Ranjit Bindra, Peter Glazer, Per Hellsund. Targeting solid tumor acidic microenvironment with an alphalex PARP inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2981.

Targeting the Hypoxic and Acidic Tumor Microenvironment with pH-Sensitive Peptides

“…Such approaches can be challenging, as they require the development of linker molecules to allow for the conjugation and intracellular delivery of said inhibitors to pHLIP while also retaining their activity against target molecules. Nonetheless, promising developments have been made in the development of a pHLIP-conjugated PARP inhibitor [ 55 , 56 ]. While the clinical use of PARP inhibitors as a monotherapy is mostly in cancers with defects in the homologous recombination pathway of DNA repair [ 57 , 58 , 59 , 60 , 61 , 62 , 63 ], PARP inhibitors may have efficacy in DNA repair proficient cancers if used in combination with DNA-damaging chemotherapy.…”

“…However, to date this approach has been limited by toxicity, primarily to the bone marrow [ 43 ]. In preclinical models, pHLIP-conjugated PARP inhibitors have been shown to synergize with DNA damaging agents such as temozolomide and irinotecan, and also have minimal normal tissue toxicity [ 55 , 56 ].…”