Abstract B60: Optimization of biologic scheduling of gemcitabine and abraxane improves treatment response compared to the standard concurrent regimen in preclinical models of pancreatic cancer
Authors: Adam R. Wolfe, Ryan Robb, Ahmad Hegazi, Duan-Liang Shyu, Laith Abushahin, Terence M. Williams
Journal: Cancer Research (2019)

Abstract Introduction: Gemcitabine (gem) and Abraxane (albumin-bound paclitaxel, abx) combination chemotherapy delivered on the same day is now one of the preferred chemotherapy regimens for metastatic and locally advanced pancreatic ductal adenocarcinoma (PDAC) based on results of the phase III MPACT clinical trial that showed improved overall survival of gem+abx compared to gem alone in the metastatic/advanced setting. Our previous published works revealed that caveolin-1 (Cav-1), the principal structural component of caveolae and mediator of endocytosis, is highly expressed in PDAC cells and associated with enhanced tumor progression and resistance to gem in PDAC preclinical models. We also found that loss of Cav-1 through genetic knockdown inhibited both PDAC cell uptake of albumin and response to albumin-based chemotherapies, i.e., abx. In addition, gem treatment resulted in a time-dependent increase in Cav-1 protein expression. Taken together, we hypothesized pretreatment with gem would increase the efficacy of the gem/abx combination via increased Cav-1 dependent albumin-bound chemotherapy uptake. Results: ASPC1 and HPAFII PDAC cell lines were exposed to gem (25-100nM) for 24-48 hours followed by a 1-hour albumin pulse and displayed a time-dependent increase in intracellular albumin via Western blotting. We next tested PDAC cell proliferation and cell survival via alamarBlue and colony formation assays with various different gem/abx scheduling combinations. HPAFII and ASPC1 cells were treated for 24 hours with the following schedules: (1) vehicle, (2) gem alone, (3) abx alone, (4) gem+abx on same day (d1gem+abx), (5) gem on day 1 and abx day 2 (d1gem_d2abx), or (6) gem on day 1, no drug on day 2 and abx on day 3 (d1gem_d3abx). Both alternative schedules of d1gem_d2abx and d1gem_d3abx had greater inhibition of proliferation and colony formation compared to the current standard of care d1gem+abx, and of all the combinations, d1gem_d3abx was the most efficacious (p&amp;lt;0.01). Genetic knockdown of Cav-1 through short-hairpin loop RNA (shRNA) in Mia-Paca2 cells resulted in reversal of the observed altered scheduling effect on cell proliferation and survival. In vivo, we compared tumor growth rates with altering gem-abx scheduling following subcutaneous injection into athymic nude mice of ASPC1 or HPAFII cells. Similar to our in vitro studies, mice were treated with either the control-vehicle or three cycles delivered over 9 days of the following gem-abx combinations: 1) d1gem+abx, 2) d1gem_d2abx, or 3) d1gem_d3abx. The d1gem_d3abx scheduling had the most significant delay in tumor growth and tumor doubling time compared to the other gem-abx schedules (p&amp;lt;0.001). Conclusion: We found 24- to 48-hour gem treatment increased albumin uptake, leading to maximal treatment efficacy with an optimized schedule of gem delivered on day 1 and abx on day 3 compared to the standard gem+abx administered on the same day. These findings support further testing of an altered and biologically optimized scheduling of gemcitabine and Abraxane. Citation Format: Adam R. Wolfe, Ryan Robb, Ahmad Hegazi, Duan-Liang Shyu, Laith Abushahin, Terence M. Williams. Optimization of biologic scheduling of gemcitabine and abraxane improves treatment response compared to the standard concurrent regimen in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B60.