Preclinical drug development in pancreatic cancer

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My laboratory aims to address the unmet medical need for more effective treatments for pancreas cancer patients by developing new cancer drugs. Scientific achievements with regard to the pursued drug development projects in the last year include: 1. Clinical translation of metarrestin. Metarrestin is a novel, first-in-class small molecule inhibitor with selective activity against the metastatic phenotype of cancer cells. It has impressive activity in pancreatic and other cancer metastasis models. Supported by NCATS' Bridging Interventional Development Gaps (BrIDGs) program IND enabling studies and manufacturing of clinical grade metarrestin capsules were completed. FDA approved the IND application in November 2019 (IND#146042). Using a safe first-in-human starting dose level of 1mg every 48 hours administered orally the phase I clinical protocol NCI 20-C-0023 is currently accruing patients with advanced solid organ cancers to determine safety and tolerability of the drug. Preclinical work has identified the translation elongation factor eEF1A2 upregulated in solid organ cancers as the molecular target of metarrestin. The factor eEF1A2 stabilizes the nucleolar PeBoW complex comprised of the components BOP1, PES1, and WDR12. Inhibition of eEF1A2 leads to rapid disassembly of the PeBoW complex, translocation of the PeBoW components into the nucleus, loss of splicing function of the large 47S ribosomal RNA precursors, loss of ribosomal pre-assembly, stalling of ribosomal biogenesis, and loss of protein synthesis function of the cell. Metarrestin binds to eEF1A2 via formation of hydrogen bonds between serine 331 and the cyclo-hexanol group of the compound. Genome-edited mice which have replaced the murine alanine on position 331 of eEF1A2 with serine and which phenocopy the neurotoxicity of metarrestin have been generated. These mouse models are used to (1) study the binding of metarrestin to its molecular target in vivo, (2) establish informative PK signatures upon treatment with metarrestin which are predictive of the neurological phenotype, such as seizures and epileptic encephalopathies, and (3) to validate tissue and circulation biomarkers predictive of neurotoxicity from cancer patients enrolled onto the phase I clinical trial to improve pharmacovigilance and the safety profile of anticancer therapy with metarrestin. These preclinical safety studies are complemented with medicinal chemistry efforts to develop a modified metarrestin derivative as a back-up candidate with improved physiochemical properties to decrease the ability to cross the blood brain barrier and lower the risk of neurological side effects. Additional in vitro studies have identified unique binding partners of eEF1A2 as well as post-translational modifications of eEF1A2 associated with metarrestin activity which will be interrogated as possible novel anti-cancer targets or biomarkers. 2. Preclinical development of peptide- and small molecule-based innate checkpoint modulators targeting CD206. A novel method of biophysical homology screening identified RP-182, a first-in-class immunomodulatory host defense peptide which is able to reprogram pro-tumor M2-like tumor associated macrophages into M1-like macrophages and which restores immune surveillance leading to anti-tumor response in a variety of animal models of cancer. RP-182 was shown to be an attractive agent for immunotherapy (anti-PD-L1) or chemotherapy treatment combinations in immunologically 'cold' cancers which currently don't respond to T cell activation via immune checkpoint inhibition. CD206 small molecule-based innate checkpoint modulators have been identified after screening large chemical libraries with a pharmacophore model derived from RP-182 docked onto the CD206 receptor. The lead series is significantly more potent than RP-182, and after SAR-guided optimization and PK evaluation has identified the phenyl-imidoazo[2,3] pyrazine-based drug candidate NCGC00413972 which is currently evaluated in pre-IND studies. The drug candidate has limited off-target activity in large panels of kinases, GPCRs, or ion channels, showed a large therapeutic window in rat toxicity studies, and is planned to undergo safety and tolerability testing in dogs prior to applying at NCATS BrIDGs program for support of IND enabling studies and production of clinical grade compound. 3. Combined stromal modulation and anti-cancer therapy in pancreatic cancer. Preclinical work in transgenic animals with pancreas cancer has shown that TGFbeta inhibition and gemcitabine cooperate to suppress tumor growth and extend survival in mice. TGFbeta inhibition-mediated stromal modulation increases perfusion via alteration of the cancer-associated fibroblast (CAF) phenotype (increases the ratio of inflammatory vs myelofibroblastic CAFs) in these tumors which rapidly returned to pre-treatment values due to intrinsic resistance mechanisms in the myelofibroblastic CAF fraction. Anti-tumor activity of TGFbeta inhibition in combination with gemcitabine is generated via immunogenic cooperativity of the two agents including the reprogramming of T regulatory cells from an effector-memory towards a naive cell phenotype. Additional preclinical work identified upregulation of the immune checkpoint PD-L1 as one of the resistance mechanisms of this approach. The clinical protocol 'A Phase IB/II Single-arm Study of M7824 (MSB0011359C) in Combination with Gemcitabine in Adults with Previously Treated Advanced Adenocarcinoma of the Pancreas' was testing the concept in patients. The study is currently on hold after the occurrence of a grade 5 immune-related adverse event.