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 and tolerable dose level of metarrestin, a first-in-class small molecule targeting genome organization in metastatic cancer cells. PK data from more than 30 patients treated with metarrestin within the first-in-human clinical study NCI 20-C-0023; NCT04222413 identified a safe regimen of a loading dose followed by a maintenance dose as safe, which achieves therapeutic levels in tumoral lesions. A robust population PK (popPK) model has been generated with a near perfect fit between measured and simulated PK. Recent preclinical work has identified a target which is selectively overexpressed in the nucleolus of cancer cells and stabilizes genome organization of ribosomal DNA genes. Metarrestin leads to phase separation of the fibrillar center (FC) and the diffuse fibrillar compartment (DFC) of the nucleolus which leads to effective halt of ribosomal biogenesis. Metarrestin causes a unique form of cell cycle arrest and synergizes with a distinct of cyclin-dependent kinase (CDK), epigenetic, and cell cycle inhibitors. The lack of p53 activation and induced cell death is a sentinel distinguishing feature of metarrestin to other polymerase I inhibitors and the reason for the favorable safety profile of metarrestin in comparison to other nucleolar inhibitors in clinical development. 2. Preclinical development and clinical translation of innate checkpoint modulators targeting CD206 on tumor associated macrophages (TAMs). 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 identified a phenyl-imidoazo[2,3] pyrazine-based small molecule drug candidate, NCGC72, which has moved into IND enabling studies. More than 2 kg of clinical grade NCGC72 have been manufactured and dose range finding studies in preparation of GLP toxicokinetic studies are currently ongoing. NCGC72 induces tumor regressions across murine and human preclinical cancer models. NCGC72 has no discernable off-target activity and showed a large therapeutic window in preclinical safety and toxicity studies due to remarkable selectivity for tumoral CD206 isoforms. The selectivity for CD206 expressed on TAMs is due to its unique glycosylation state which is characterized by decreased sialylation of select amino acid residues in the vicinity of the binding region of NCGC72 allowing access of the small molecule to the receptor. The lack of activation of immune cells residing in normal organs is a distinguishing a feature to immune checkpoint inhibition with PD-1/PD-L1 or CTLA-4 blockade. NCGC72 has also been evaluated in a dedicated phase I study in sarcoma-bearing dogs and found to be safe with early signals of anti-tumor activity. Reprogramming of CD206high, M2-like TAMs towards a proinflammatory phenotype via the induction of an interferon type I response is the main anti-tumor mechanism as blockade of NCGC72-mediated M2-like cell killing recruits TAMs towards enhanced cancer cell phagocytosis and tumor control. Current work expanding on these findings is studying (1) rationale designed drug combinations of immune-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 evaluated NCGC72 in a preclinical model of proliferative diabetic retinopathy where NCGC72 substantially reduced sub-retinal fibrosis and retinal detachments, causes of blindness in diabetic retinopathy patients. In a preclinical non-alcoholic steatohepatitis (NASH) and liver fibrosis, NCGC72 improved function of CD2096 restorative macrophages reducing liver damage and dysfunction. 3. Stromal reprogramming of solid organ cancers via human relaxin receptor 1 (hRXFP1) agonism. RXFP1 is expressed on multiple stromal cell populations including cancer-associated fibroblasts, tumor associated macrophages, or endothelial cells. Using an orally available, small molecule RXFP1 preclinical development candidate, treatment of Ras-driven murine pancreatic cancers in a mouse model where the murine relaxin receptor 1 had been replaced with the human version of RXFP1 led to effective tumor control, in particular in combination with anti-PD-L1 immune checkpoint inhibition. Using a combination of spatial profiling and single cell sequencing technologies, current efforts focus on the delineation of cellular targets and cell type-specific mechanism of action of the drug candidate.