Preclinical drug development in pancreatic cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

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; NCT04222413 is currently accruing patients with advanced solid organ cancers to determine safety and tolerability of the drug. Preliminary PK data from the first patients treated with metarrestin appear to indicate that after multiple dosing metarrestin reaches therapeutic levels in plasma. It is expected that the current dosing schedule will be modified to twice a week or once weekly dosing to reduce drug accumulation of metarrestin and optimize exposure. 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, previously not identified as a cancer target, which is 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 of the large 47S ribosomal RNA precursors, loss of rRNA processing function, 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 and binding of metarrestin to eEF1A2 is guided by post-translational modification which differ in metastatic cancer cells vs normal cells. 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 and are used to (1) study the binding of metarrestin to its molecular target in vivo and (2) establish informative PK signatures which are predictive of the neurological phenotype, such as seizures and epileptic encephalopathies to improve pharmacovigilance and the safety profile of anticancer therapy with metarrestin. Medicinal chemistry work has been started to develop a back-up candidate with decrease 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 future biomarkers or leads for rationale-designed combination studies. 2. Preclinical development of small molecule-based innate checkpoint modulators targeting CD206 on TAMs. The first-in-class synthetic host defense peptide RP-182 targets the mannose receptor CD206 on M2-like TAMs and was shown by our group to be an attractive agent for immunotherapy in immunologically 'cold' cancers which currently don't respond to T cell activation via immune checkpoint inhibition. In silico screening of large chemical libraries with a pharmacophore model derived from RP-182 docked onto the CD206 receptor has identified the phenyl-imidazo[2,3] pyrazine-based drug candidate NCGC00413972. NCGC00413972 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, tolerability, and efficacy testing in sarcoma-bearing dogs prior to applying for support of IND enabling studies and production of clinical grade compound. Recent work showed that NCGC00413972 has dual function; via activation of canonical NF-kB signaling and an early inflammatory gene response the candidate induces M2 macrophage killing. Internalized NCGC00413972 induces an interferon type I response which reprograms M2 to M1-like macrophages, induces cancer cell phagocytosis, and anti-tumor activity. Additional mechanism of action studies will inform rationale-designed combinations to enhance the activity of NCGC00413972. 3. 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 'Immune Checkpoint Inhibitor M7824 and the Immunocytokine M9241 in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Advanced Pancreas Cancer' (NCI 20-C-0074; NCT04327986) is testing the concept of overcoming resistance to TGFbeta inhibition via the addition of pro-immunogenic agents including IL-12 agonists, PD-L1 checkpoint inhibitors, and stereotactic radiation therapy.