Abstract 369: Gemcitabine nab-paclitaxel combination with DMAPT in PDAC cachexia
Authors: Counts Brittany , Jean Sephora , Wang Reggie , Zimmers Teresa 
Published: April 2023

Background: Cachexia is the progressive, unintentional wasting of muscle and adipose tissue caused by tumors. Cancer cachexia affects &gt;80% of patients with pancreatic ductal adenocarcinoma (PDAC). Certain chemotherapy regimens cause debilitation in patients and muscle and fat wasting in mouse models. Gemcitabine with nab-paclitaxel (GemNP) is a first line treatment for PDAC. Whether GemNP promotes cachexia is unknown. Muscle wasting in cancer cachexia has been functionally linked to NF-κB, which can be induced by chemotherapies and is active in PDAC tumors. Among other functions, NF-κB induces expression of Interleukin-6 (IL-6), a major mediator of cancer cachexia. DMAPT is a small molecule NF-κB inhibitor. In prior work, DMAPT plus Gem reduced tumor burden in a genetic model of pancreatic cancer and separately, prevented muscle wasting in a genetic model of mammary cancer. Therefore, the purpose of our study was to determine whether GemNP promotes cachexia and whether DMAPT could reduce tumor burden and/or cachexia in PDAC, potentially through reducing IL-6 expression.

Methods: In our in vitro model, conditioned media (CM) from KPC pancreatic cancer cells derived from the KrasG12D;Trp53R172H;Pdx1-Cre mouse, induces wasting of C2C12 myotubes. Thus, myotubes were treated with 50% KPC-CM or control CM and supplemented with 0, 5, or 10uM DMAPT for 48hrs. For in vivo modeling of PDAC cachexia, 12-week-old male C57BL/6J mice were orthotopically implanted with 5x104 KPC cells or KPC cells deleted for IL6 (KPC-IL6KO) cells; controls underwent sham surgery. Starting on day 4, every 6 days tumor-bearing mice were given 120 mg/kg gemcitabine and 10 mg/kg nab-paclitaxel (GemNP) for four rounds, then gemcitabine only for subsequent rounds, with or without 100mg/kg DMAPT (by gavage 5 days/week). Controls received vehicle only.

Results: DMAPT prevented atrophy in KPC-CM treated myotubes. In vivo, GemNP increased median survival, to 23.5d in KPC + GemNP mice versus 17d in untreated KPC mice (P&lt;0.001). GemNP + DMAPT increased survival (25d) compared to untreated KPC (P&lt;0.001), but was similar to KPC + GemNP alone (P=0.693). There were no differences in tumor mass at euthanasia. All KPC groups lost significant body weight and fat mass compared to sham controls. In mice with KPC IL-6KO tumors, GemNP increased survival, with median survival of 39d in KPC-IL6KO + GemNP mice compared with 30d in untreated KPC-IL6KO (P&lt;0.001). GemNP + DMAPT increased survival (35 d in KPC IL-6KO) compared to untreated KPC-IL6KO (P&lt;0.001), but was similar to KPC IL-6KO + GemNP (P=0.276). There was a trend for GemNP + DMAPT to have smaller KPC-IL6KO tumors compared to GemNP (p=0.055).

Conclusion: Regardless of IL-6 expression from tumor cells, treatment with GemNP improved survival in orthotopic PDAC without exacerbating cachexia. DMAPT did not extend survival above GemNP alone. Despite promising in vitro data and prior published work, DMAPT was not efficacious in reducing tumor growth or treating PDAC cachexia in this model.

Citation Format: Brittany Counts, Sephora Jean, Reggie Wang, Teresa Zimmers. Gemcitabine nab-paclitaxel combination with DMAPT in PDAC cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 369.