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 patients afflicted by pancreas and other solid organ cancers 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. 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 six 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 exceeding efficacious levels of prior preclinical efficacy studies in plasma and do not carry risk(s) of drug accumulation. No clinical dose-limiting toxicities have occurred so far in patients treated with metarrestin. However, two patients had prolongations of their QTc intervals observed during EKG monitoring which are currently followed as possible metarrestin-related suspected unexpected serious adverse reaction (SUSAR). Recent preclinical work has shown that metarrestin inhibits polymerase I transcription via disruption of liquid phase-phase separation (LPPS) in the nucleolus. LPPS is regulated by biomolecular condensates (BMCs) which direct the unique ultrastructure of the nucleolus necessary for rRNA synthesis, rRNA processing, and the assembly of the SSU processome. Reduced 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, leads to disassembly of the PNC and translocation of PNC components into the nucleoplasm. PNCTR transcript levels, genomic alterations of the PNCTR locus on chromosomes 21, PNC prevalence as well as mutations in intrinsically disordered regions (IDRs) of nucleolar proteins which are involved in the regulation of LPPS are currently evaluated as biomarkers to predict response to metarrestin. 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 clinical testing, a NIH FAES course summarizing key milestones in translational processes of metarrestin's development has been designed and is now in its third year. 2. Preclinical development and clinical translation of small molecule-based innate checkpoint modulators targeting CD206 on tumor associated macrophages (TAMs). Prior work of ours has shown that the mannose receptor CD206 on M2-like TAMs functions as an immune checkpoint. CD206 activation reprograms TAMs from a pro-tumor, immune suppressive to an anti-tumor, inflammatory phenotype and CD206 ligation is able to reinvigorate innate anti-tumor responses via direct cancer cell phagocytosis. Due to its restricted expression, 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 has via in silico screening of large chemical libraries identified a phenyl-imidoazo[2,3] pyrazine-based small molecule drug candidate, NCGC72, which has recently been selected for IND enabling studies and clinical translation by the Therapeutic Development Branch (TDB), NCATS. NCGC72 induces tumor regressions in murine and human preclinical cancer models. NCGC72 has limited off-target activity and showed a large therapeutic window in preclinical safety and toxicity studies. NCGC72 is currently evaluated in a dedicated phase I/II study for safety, tolerability, and efficacy in sarcoma-bearing dogs. After acceptance of NCGC72 as a clinical candidate by the TDB, NCATS, manufacturing of GMP drug substance for both GLP safety and toxicokinetic studies and clinical grade product for human phase I testing has commenced with IND filing estimated in 2025 and start of clinical testing in 2026. Additional preclinical work has focused on NCGC72's dual mechanism of action of (1) M2-like macrophage killing and (2) the reprogramming of alternatively activated, M2-like TAMs into a proinflammatory phenotype via the induction of an interferon type I response. Current mechanism of action studies have shown that blockade of NCGC72-mediated M2-like cell killing recruits TAMs for enhanced reprogramming, cancer cell phagocytosis, and tumor control, and that the interferon type I response triggered by NCGC72, which is essential for M2-to-M1-like switching, induces a select number of epigenetic changes releasing repression of closed chromatin of promotors and enhancers in alternatively activated, M2-like TAMs. Current work expanding on these findings is studying (1) rationale designed drug combinations of immuno oncology agents with NCGC72, and (2) molecular markers to select tumors most likely to respond to NCGC72. Spurned by recent reports that CD206 positive macrophages mediate disease-causing processes in non-malignant conditions like eye disease or type II diabetes, we previously evaluated NCGC72 in a preclinical model of proliferative diabetic retinopathy. NCGC72 substantially reduced sub-retinal fibrosis and vitriol hemorrhages, causes of blindness in diabetic retinopathy. To extend possible indications of NCI's proprietary CD206 small molecule technology NCGC72 for the treatment of non-malignant diseases further, we are currently evaluating NCGC72 in a preclinical model of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis.