Preclinical drug development in pancreatic cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

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. Identification of a clinically safe dose level of metarrestin, a first-in-class small molecule targeting genome organization in metastatic cancer cells. 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 preclinical pancreatic and other cancer metastasis models. FDA approved the IND application in November 2019 (IND#146042). Metarrestin is currently administered to patients with advanced malignancies in escalating doses to determine safety and tolerability of the drug. PK data from the first two cohorts of patients treated with metarrestin identified a regimen of a loading dose followed by a maintenance dose as safe which achieves human-equivalent therapeutic levels of prior preclinical efficacy studies in plasma and does not carry risk(s) of drug accumulation upon multiple dose administration. No dose-limiting toxicities have occurred so far in patients treated with metarrestin. However, two patients had prolongations of their QTc intervals during EKG monitoring which was reported as metarrestin-related suspected unexpected serious adverse reaction (SUSAR) and is currently actively followed. Preclinical work has shown that metarrestin inhibits polymerase I transcription and reduces expression levels of the pyrimidine-rich non-coding transcript (PNCTR) long non-coding RNA (lnRNA) which is an essential scaffold of the PNC and which is transcribed by polymerase I. Loss of PNCTR transcripts leads to disassembly of the PNC, translocation of PNC components into the nucleoplasm, and separation of ultrastructural components of the nucleolus due to loss of physiologic phase-phase separation. PNCTR transcript levels, genomic alterations of the PNCTR locus on chromosomes 13, 14, 15, 21 and 22, PNC prevalence as well as pol I transcript ratios are currently evaluated as biomarkers to predict response to metarrestin. Medicinal chemistry work has commenced to develop a back-up candidate of metarrestin with decreased ability to cross the blood brain barrier and lower the risk of neurological side effects. Recognizing the educational value of the successful clinical translation of metarrestin for essential processes of drug development from the initial high-content screen testing chemical compounds to disassemble the PNC, the medicinal chemistry campaign, preclinical work, IND enabling studies, to now clinical testing, an online course summarizing key milestones in translational processes of metarrestin's development has been designed and is now in its second year. 2. Preclinical development of small molecule-based innate checkpoint modulators targeting CD206 on TAMs. Prior work of ours has shown that the mannose receptor CD206 on M2-like TAMs functions as an immune checkpoint. CD206 activation via either peptide- or small molecule leads is able to reprogram TAMs from a pro-tumor, immune suppressive to an anti-tumor, inflammatory phenotype able to reinvigorate innate anti-tumor responses via direct cancer cell phagocytosis. CD206 is an attractive target for novel cancer immunotherapy in immunologically 'cold' cancers which currently do not respond to T cell activation via immune checkpoint inhibition. Our group previously described a first-in-class, synthetic host defense peptide RP-182 which activates CD206 and reprograms TAM in solid organ tumors. In silico screening of large chemical libraries with a pharmacophore model derived from RP-182 docked onto the CD206 receptor interface has identified the phenyl-imidoazo[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. After successful competition for resources from CCR's Drug Development Consortium (DDC) for further preclinical development and clinical translation a dedicated phase I/II study evaluating safety, tolerability, and efficacy in sarcoma-bearing dogs has commenced prior to applying for support of IND enabling studies. A scale-up synthesis scheme of NCGC00413972 for the production of clinical grade drug substance has been devised. Additional preclinical work has shown that NCGC00413972 has dual function; via activation of canonical NF-kB signaling and an early inflammatory gene response NCGC00413972 induces M2 macrophage killing. Internalized CD206 receptors after treatment with NCGC00413972 on the other hand induce an interferon type I response which reprograms M2 to M1-like macrophages, induces cancer cell phagocytosis, and anti-tumor activity. Current mechanism of action studies to increase efficacy of CD206 innate immune checkpoint therapy via NCGC00413972 explore (1) combinations of immuno oncology agents with synergistic mechanisms as NCGC00413972, and (2) selection of tumors with CD206 positive immune profiles most likely to respond to NCGC00413972. Spurned by recent reports that CD206 positive macrophages mediate disease-causing processes in non-malignant conditions like eye disease, infectious diseases, or type II diabetes, we have evaluated NCGC00413972 in a preclinical model of proliferative diabetic retinopathy. NCGC00413972 substantially reduced sub-retinal fibrosis, the cause of retinal detachment, vitriol hemorrhages, and blindness in diabetic retinopathy. As a first indication for CD206 checkpoint modulators outside oncology we protected a possible role of NCI's proprietary CD206 small molecule technology NCGC00413972 in the treatment of diabetic retinopathy via filing of Prov Patent Appl E-167-2021 (MBHB 21-0949-PRO) METHODS AND COMPOSITIONS FOR THE TREATMENT FOR INFLAMMATION AND FIBROSIS IN RETINAL NEOVASCULAR DISEASES.