Preclinical drug development in pancreatic cancer

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My laboratory aims to address the unmet medical need of 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. Preclinical and clinical development of metarrestin (U.S. Patent filing E-114-2018-0-US-01 (738874 BIO.0353-18) 'Metarrestin for the Treatment of Pancreas Cancer'). Metarrestin is a novel 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 an IND package including GLP toxicokinetic studies in rodent and non-rodent species as well as manufacturing of clinical grade metarrestin capsules has been completed. PK studies in five species showed metarrestin to be a low clearance compound (under review) with high bioavailability and biodistribution with drug-induced neurological events including seizures as the lead clinical toxicity of the compound. A safe first-in-human starting dose level of 1mg every 48 hours administered orally has been calculated which is in, or close to, the therapeutic range of metarrestin predicated from preclinical studies. A phase I protocol has been approved by NCI CCRs Scientific Review Committee and IND filing is anticipated in Q3 2019. Preclinical work identified the translation elongation factor eEF1A2 upregulated in cancer as the molecular target of metarrestin and interference with ribosomal biogenesis as a novel mechanism of action induced by the drug. The mechanism of action of metarrestin has been linked to post-translational modifications of eEF1A2 and disruption of the PES1-BOP1 complex involved in rRNA processing and ribosome formation. Genome-edited mice including eEF1A2 knockout mice which phenocopy the clinical phenotype the neurotoxicity of metarrestin have been generated. These mouse models are planned to be used to (1) establish informative PK/TK signatures upon treatment with metarrestin which are predictive of the neurological phenotypes, such as seizures and epileptic encephalopathies, emerging as possible side effects of metarrestin treatment; (2) to validate tissue and circulation biomarkers, as well as neurological and neuropathological pattern, derived from phenotypical assessment after treatment with metarrestin; and (3) to interrogate serum from cancer patients enrolled into phase I clinical testing for PK/PD correlations and serum biomarker changes predictive of imminent neurotoxicity observed in mice to improve pharmacovigilance and 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. 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 which restores immune surveillance leading to anti-tumor response in a variety of animal models of cancer (License number: L-051-2017/0; issued U.S. patent; 'Peptide-Based Methods for Treating Pancreatic Cancer'). A bioanalytical method to measure such synthetic short HDPs in complex biological specimens for PK and toxicokinetic studies has been developed (under review). 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. Formulation and PK studies are under way to evaluate RP-182 as a preclinical first-in-class innate checkpoint drug candidate. Based on prior work with RP-182, CD206 small molecule innate checkpoint modulators have been identified after screening large chemical libraries with a pharmacophore model derived from RP-182 docked onto CD206. The lead series is significantly more potent than RP-182, and has undergone SAR-guided optimization and PK evaluation which showed excellent biodistribution and a preliminary safe toxicity profile. An Employee Invention Report (NIH Ref.: E-105-2019; 'Small Molecules with Selective Activity Against the M2 Phenotype of Macrophages') has been filed and following delineation of the chemical space of the lead series on its target CD206 a filing for Composition of Matter is planned. New drug designs with RP-182 are manufactured which include the coupling of RP-182 to PD-1/PD-L1 antibodies generated via [3+2] cycloaddition (click- de-click-like reaction) followed by a retro- Diels-Alder reaction or to a scaffold in preparation of creating tripod immuno-oncology agents (coupled immunocytokines, checkpoint regulators, and RP-182 to one scaffold). 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 myelofibrotic CAFs) in these tumors which rapidly returns to pre-treatment values creating uncertainty about during, and possibly rationale, for prolonged administration of stromal modulation therapy. The conducted preclinical work also 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' is testing the concept in patients. 4. KRAS-mutational isotype directed molecular therapy. A CTEP-sponsored phase II pilot study treating patients whose tumors harbor G12R KRAS isoform somatic variants (NCT03040986; Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations) has not proceeded to the 2nd stage due to lack of efficacy of the selected MEK inhibitor. This clinical study was a direct translation of our laboratory findings of increased sensitivity of KRAS G12R mutational isoform-harboring cell lines and patient-derived xenotransplantation models. 5. Target deconvolution of a multikinase inhibitor with anti-metastatic properties identifies TAOK3 as a key contributor to a cancer stem cell-like phenotype. While this work adds to the understanding how to target cancer stem-like cells, due to due concerns about the toxicity of the multikinase inhibitor NCGC00188382 (inhibitor #1), the molecule was not selected for further preclinical studies or clinical translation.