Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are among the leading cancer killers with 47,000 deaths from PDAC and 53,000 deaths from metastatic CRC estimated in US 2020. PDAC and CRC genomes frequently contain deletions of tumor suppressor genes, including SMAD4 which is deleted in nearly 33% of PDAC cases and 10% of advanced CRC. When cancer cells sustain deletion of SMAD4, nearby genes that may play essential cell functions are invariably co-deleted. Cancer cells survive these co-deletions due to the presence of functionally redundant family members (known as paralogs) which reside elsewhere in the genome. We hypothesized that inhibiting the non-deleted paralogs can...

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Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are among the leading cancer killers with 47,000 deaths from PDAC and 53,000 deaths from metastatic CRC estimated in US 2020. PDAC and CRC genomes frequently contain deletions of tumor suppressor genes, including SMAD4 which is deleted in nearly 33% of PDAC cases and 10% of advanced CRC. When cancer cells sustain deletion of SMAD4, nearby genes that may play essential cell functions are invariably co-deleted. Cancer cells survive these co-deletions due to the presence of functionally redundant family members (known as paralogs) which reside elsewhere in the genome. We hypothesized that inhibiting the non-deleted paralogs can result in cancer-specific vulnerabilities in SMAD4-deleted PDAC and CRC that carry these co-deletions, yet spare normal cells which have intact SMAD4 loci. In SMAD4-null PDAC and CRC, we have identified seven co-deleted genes in the SMAD4 locus. Five of these (MAPK4, ELAC1, ACAA2, LMAN1 and TXNL1) have paralog(s) which presumably compensate the co-deleted genes’ essential functions. We will use a powerful gene editing tool (enCas12a) to delete each paralog to test the collateral lethal relationship between each of the five deleted gene/paralog pairs. For the other two co-deleted genes, CTIF and LIPG, there are no clear paralogs. Therefore, for these co-deletions, we will screen all genes in the genome using the enCas12a platform to identify their functional partners (so-called synthetic lethal partners). All the potential targets will be further verified in multiple cell culture systems and mouse tumor models. Although beyond the scope of this grant, any confirmed targets from these screens will be enlisted into in-depth validation and drug discovery efforts for cancers harboring SMAD4 deletion. We believe that this proposed research will significantly increase the pool of novel drug targets for PDAC and CRC patients who are failing today’s standard of care.

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