The University of Texas MD Anderson Cancer Center—Targeted Therapeutics for Ovarian Cancer and its Microenvironment – Treatment and Theoretical Modeling
Principal Investigators: Gabriel Lopez-Berestein, M.D.
Co-Investigators: Anil Sood, M.D., Bulent Ozpolat, M.D., Ph.D., David Volk, Ph.D., Vittorio Cristini, Ph.D., Zhihui Wang, Ph.D., Lokesh sRao, Ph.D., and Sunila Pradeep, Ph.D.
Ovarian cancer, especially high-grade serous ovarian cancer (HGSOC), is the deadliest gynecological cancer with 50-70% five-year mortality rates. Traditional therapy for ovarian cancer has included surgery followed by chemotherapy with platinum/taxane-based regimens. Although most ovarian cancer is initially chemosensitive, recurrence of the disease is common due to development of resistance and significant intra-tumoral heterogenity, both of which contribute to poor prognosis and high mortality rates in patients. Recent clinical and experimental evidence indicate that the monocyte-macrophage axis and tumor-associated macrophages (TAMs), which make up a portion of the tumor microenvironment, play a significant role in tumor growth and progression by contributing to angiogenesis, invasion and metastasis, and drug resistance, particularly in ovarian cancer and especially in HGSOC. Overall our data indicate that in contrast to conventional drugs that target only tumor cells, targeting the tumor microenvironment is required to achieve maximal anti-tumor efficacy. The use of nanoparticles incorporating specific gene silencing molecules (i.e., siRNA) targeting the tumor or its microenvironment is a particularly attractive approach for overcoming obstacles and reprogramming the tumor microenvironment by silencing critical molecular targets. In this study, we will test the hypothesis that the blockade of tumor and tumor microenvironment interactions by therapeutic nanoparticles will provide significant antitumor activity and enhance the efficacy of current regimens in ovarian cancer. Thus, we will determine the mechanism of TAM regulation. We will also determine the biological and therapeutic efficacy of targeting MMA/TAMs using highly targeted dual effect nanoparticles in ovarian cancer models. These include (1) long-acting, slow-release dual assembly NPs (DANPs), and (2) serum resistant highly specific AXL-receptor binding aptamers.
The proposed approaches offer nanotherapeutic formulations targeting multiple components of the tumor and its microenvironment. Specifically, in aim 1 we are focusing on reprograming the tumor microenvironment by eliminating tumor-promoting TAMs using long-acting, slow release DANPs encapsulating an siRNA for a validated target. This will affect the regulatory cascade of these cells and their impact on inflammation, stromal reactions, and eventual tumor growth. In aim 2, we will develop a multiscale 3D mathematical model to evaluate therapeutic efficacy of the nanoparticles with or without AXL aptamers on the nanoparticle surface, and with or without chemotherapy. The model will be used to understand and predict the effects of this nanoparticle-based treatment on MMA cell accumulation, angiogenesis, and tumor progression in HGSOC models. Finally, in aim 3 we will identify specific AXL aptamers and optimize their chemical modifications to determine which ones enhance nanoparticle effects will maintaining good selectivity and targeting. We will also use multipronged dosing schedules to determine optimal dosing regimens that provide effective pharmacological and efficacy profiles.
The team has expertise in nanomedicine, cancer biology, RNA-based therapeutics, liposomes, aptamer development, and mathematical modeling.