Activity of dual BET and CDK9 inhibition in murine models of pancreatic ductal adenocarcinoma

Background : Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer related mortality in the U.S. with a 13% 5-year survival rate. Acquired resistance plays a critical role in progression, however targeted therapeutics have been developed for rare molecular subsets. Prior phenotypic screening efforts showed activity of bromodomain and extraterminal (BET) and cyclin dependent kinase 9 (CDK9) in PDAC organoid models. Here, we examine two independent heterotopic patient derived xenograft (PDX) murine models for the activity of BET inhibitor (ZEN3694) and CDK9 inhibitor (VIP152). Methods : Immunodeficient Rag2 KO /II2rg KO (R2G2) mice received subcutaneous injections of two PDAC models, PDX1 and PDX2. The models shared pathologic variants including KRAS G12D , MTAP loss, and CDKN2A/B loss. PDX2 had concurrent loss of SMAD4. Mice colonies were treated with ZEN3694 (50 mg/kg), VIP152 (6 mg/kg), or the combination. VIP152 was administered once per week at the start of each treatment cycle and ZEN3694 was administered for five consecutive days followed by a two-day rest period. Four seven-day cycles were administered with primary endpoint of tumor volume comparison at day 28. Body weight and tumor volumes were measured biweekly by a blinded co-investigator. Toxicity was assessed by animal condition, complete blood count (CBC), and comprehensive metabolic panel (CMP) testing. Results : All treatments were well tolerated, with no treatment group achieving weight loss >20% over the study duration. For PDX1, median weights increased by +1.21%, with non-significant change in weight for the combination of VIP152 with ZEN3694 (-14.1%). For PDX2, median weights decreased by -4.17%, with non-significant change in weight for the combination group (-8.85%). CBC and CMP results reveal no significant differences at terminal draws across treatment groups. For PDX1, median tumor growth was found to increase by +308%, with non-significant change in growth for VIP152 (+223%) or ZEN3694 (+210%), while the combination of VIP152 with ZEN3694 yielded growth arrest (-1.56%, p<0.036). For PDX2, median tumor growth was found to increase by +1,127%, with non-significant change in growth for VIP152 (+1,083%) or ZEN3694 (+643%), while the combination group yielded significant reduction in growth (+375%, p<0.024). Conclusions : Across two independent PDAC PDX models, ZEN3694 and VIP152 yield tumor growth inhibition. All treatments were well tolerated in two independent PDAC models, PDX1and PDX2. Ongoing studies are analyzing early timepoints for a putative mechanism involving transient disruption in the activation of RNA polymerase II. Parallel analysis is examining the selectivity of this disruption in cancer tissues as opposed to background liver to index the selectivity of this drug combination in cancer types, including those where Myc can be dynamically overexpressed in response to therapeutic challenge.