Abstract 6263: Hypoxia-targeting prodrug approach for multimodal chemotherapy and immunogenic cell death in aggressive triple negative breast cancer
Authors: Bhise Ketki , Sau Samaresh , Rauf Mohd Ahmar , Rishi Arun K. , Iyer Arun K. 
Published: September 2020

Immune checkpoint blockade molecules, including antibodies against PD-1 and PD-L1 have gained much clinical recognition in the past few years. These strategies include harnessing the host's immune system to invade cancer cells by inhibiting the interaction between PD-1 and its ligand, PD-L1, thereby facilitating the activation of CD8+ T cells to mount an attack on cancer cells. Triple Negative Breast Cancer (TNBC) accounts for 10-20% of the total breast carcinoma cases. There is no FDA-approved targeted therapy for TNBC due to lack of the major biomarkers: estrogen, progesterone and HER-2. TNBC is difficult to treat, with a high rate of metastasis to nearby organs. We have identified the role of a hypoxia biomarker, carbonic anhydrase IX (CAIX) in proliferation and metastasis of TNBC. Based on this observation, we developed a CAIX-targeted Doxorubicin (Dox) prodrug nanoparticle, abbreviated as CAIX-Dox-NP. CAIX-Dox-NP can deliver the chemotherapeutic, Dox payload selectively in hypoxic tumor microenvironment, thus reducing Dox-associated cardiotoxicity. Most of the advanced stages TNBC solid tumors present themselves with oxygen-deficient, vascularized and matrix-rich core which is impermeable to most of the chemotherapy drugs. CAIX-Dox-NP has the ability to penetrate deep into the TNBC and kill epithelial tumor cells as well as tumor-growth promoting T-cells. CAIX-Dox-NP showed greater penetration in the core of hypoxic TNBC spheroid. Recent studies showed that Immunogenic Cell Death (ICD) has vital role in resurrecting the CD8+ T-cells mediated tumor killing. Combination of anti-PD-1 with inducers of ICD like Dox accentuate the ability of CD8+ T cells in killing of cancer cells. Our approach is to utilize CAIX-Dox for achieving CAIX-mediated targeted delivery and multimodal chemotherapy in addition to induction of ICD. Preliminary studies with CAIX-Dox has profound effect of killing TNBC cells, 4T1, through induction of early phase apoptosis. The Western Blot analysis in 4T1 treated with CAIX-Dox has proved the significant upregulation of ICD biomarkers, HMGB1 and calreticulin, by greater than 3-fold compared to control. To improve the bioavailability of CAIX-Dox, we developed CAIX-Dox-NP that can hitchhike on the circulating plasma albumin. The nanoparticles travel to the tumor and deliver the CAIX-Dox at the hypoxic core of TNBC, resulting in induction of apoptosis and ICD. Inspired from this outcome, we are developing a model for coculture of cancer and T-cells for evaluating if CAIX-Dox treatment can reeducate T-cells in killing cancer cells through ICD pathway.

Citation Format: Ketki Bhise, Samaresh Sau, Mohd Ahmar Rauf, Arun K. Rishi, Arun K. Iyer. Hypoxia-targeting prodrug approach for multimodal chemotherapy and immunogenic cell death in aggressive triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6263.