Abstract P3-10-21: Preclinical evaluation of a novel phospholipid drug conjugate with a combretastatin A-4 analogue for improved breast cancer therapy

Abstract

Abstract Purpose: Breast cancer (BrCa) is the most common invasive cancer in women globally and the second most common cause of death from cancer in women in the US. Combretastatin A-4 (CA4) and associated analogues have been shown to be potent cytotoxins and inhibitors of tumor blood flow. However, CA4 and its analogues have not progressed rapidly through clinical trials. It has been shown that with some of the CA4 analogues, incomplete disruption of the vasculature and/or proangiogenic factors around the tumor result in survival of the cap portion of the tumor and future progression. Additionally, the over expression of MDR-1 gene which encodes for P-glycoprotein (Pgp) efflux pumps which is overexpressed in many cancer cells has been shown to limit the activity of these molecules. Phospholipid-drug conjugates (PDCs) are a modality designed to selectively deliver molecules to the tumor or tumor microenvironment, significantly increasing intracellular or local concentrations. In the current study, we established a series of PDCs using a single CA4 analogue (CA4A) conjugated to our phospholipid ether targeting platform (PDC-CA4A) utilizing different peptide linkers that allow for facile targeting and release of the CA4A payload. In this study, we evaluated the in vitro and in vivo therapeutic potential of different PDC-CA4A molecules. Methods: In vitro assessment of cellular internalization, accumulation and release of the payload was evaluated via mass spectrometry in A549 and normal human dermal fibroblast (NHDFs) cells. Additionally, in vitro assessment of cytotoxicity was performed in A549, MCF7, HCT116 and NHDFs with fifty percent inhibitory concentrations (IC50s) being determined for each. Subcutaneous HCT116 and MCF7 xenograft tumor models were used to evaluate the antitumor efficacy of several PDC-CA4A molecules compared with the free CA4A molecule. Results: All PDC-CA4A molecules showed excellent uptake, accumulation and release of the CA4A payload in the A549 cell line. Uptake was detected at the first time point tested (30 minutes) after exposure and continued through 24 hours. A steady state of release of the payload and new PDC-CA4A molecules entering the cell was reached 3 hours post exposure. Cytotoxicity tests demonstrated IC50s ranging from nanomolar to micromolar concentration depending upon the linker being utilized. In vivo, PDC-CA4A-109 (specific molecule) demonstrated statistically significant benefit over both free CA4A and the positive control group. Conclusion: Our results suggest that PDC-CA4A-109 is a promising antitumor agent to treat both breast cancer and colorectal cancers. Further clinical study is warranted to evaluate the safety and feasibility of PDC-CA4A-109 as a novel targeted therapy. Citation Format: Jarrod Longcor, Randall Hoover, Mark Wolf. Preclinical evaluation of a novel phospholipid drug conjugate with a combretastatin A-4 analogue for improved breast cancer therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-21.