Discovery Day 2018

Chen Qian’s Abstract:
Targeting the chemokine receptor CX3CR1 with novel small-molecule antagonists as a therapeutic approach for metastatic disease.
We have previously shown that the chemokine receptor CX3CR1 is implicated in the metastatic seeding of prostate[1] and breast cancer cells [2] and that JMS-17-2 a novel small-molecule antagonists of this receptor effectively contains both number of lesions and total tumor burden in animal models of metastatic disease [3]. Here we report that FX-68, an improved CX3CR1 antagonist and our current lead compound, is at least as effective as JMS-17-2 [4] and also impairs the seeding of additional tumors by Circulating Tumor Cells (CTCs) departing from existing metastases. Notably, the CTCs unable to reseed and forced to remain longer in the blood eventually succumb to apoptotic death. Furthermore, we demonstrate that prolonging the permanence of CTCs in the blood – by targeting CX3CR1 with FX-68 – improved exposure of cancer cells to the chemotherapy drugs Doxorubicin and Docetaxel, with the latter exerting an additive inhibitory effect on tumor progression and extending overall survival. Importantly, we provide evidence that cancer cells seeding the skeleton despite the inhibition of CX3CR1 failed to develop into tumors, suggesting a role for CX3CR1 in the metastasis-initiating properties of breast cancer cells. In summary, our results strongly support the development of CX3CR1 antagonists and promoting their clinical use, as this approach will provide novel and effective tools to contain the progression of metastatic disease in patients.

Ramanpreet Kaur’s Abstract:
Prostate cancer (PCa) is the second most frequently diagnosed cancer and its progression into metastatic disease is the cause of mortality in 60% of men diagnosed. To combat this, the study of metastatic dissemination and the tumor microenvironment, which allows the cancer cells to grow and survive at distant sites, is essential. Our lab has shown that PCa cells express the chemokine receptor CX3CR1 and are attracted to bone-derived CX3CL1 (or fractalkine/FKN), implicating the CX3CR1-FKN axis in PCa metastasis. Furthermore, the bone microenvironment, consisting of a heterogeneous population of M1- and M2- polarized tumor-associated macrophages (TAMs), is implicated in tumor progression. These cells are in close proximity to cancer cells and are responsible for releasing growth factors, chemokines, and other inflammatory mediators that influence tumorigenesis. We show that PCa cells and macrophages express the CX3CR1 receptor, and this receptor is engaged upon Fractalkine treatment. The subsequent downstream signaling is mitigated with CX3CR1 antagonist treatment. We show, with our in vivo mouse model of cancer cell dissemination, that our novel CX3CR1 antagonist can block initial seeding to the skeleton and because macrophages express the CX3CR1 receptor, we may potentially hinder TAM accumulation to the metastatic microenvironment. We hypothesize that the CX3CR1-FKN axis, along with the interaction of tumor associated macrophages, drives the metastatic potential of PCa cells and thus modulation of these interactions, through antagonists of CX3CR1, can influence the progression of PCa metastasis.

Anthony DiNatale’s Abstract:
The molecular mechanism of the regulation of IL-1β expression in prostate cancer progression.
The universal understanding that prostate cancer progression is dependent on an Androgen Receptor (AR) mediated transcriptome profile has led to focused development of therapeutics. While this has resulted in moderate success, patients being treated with androgen deprivation therapy (ADT), therefore blocking the activity of the AR, often progress to castration resistant prostate cancer (CRPC) with metastases. Recently, we have demonstrated that prostate metastases in the bone are heterogeneous in respect to AR status, with a significant percentage of cells lacking the AR (ARNeg). Further understanding of the molecular profile of ARNeg cells, along with the mechanism of their emergence, is necessary to allow the generation of new therapeutics for metastatic CRPC (mCRPC). We have shown that ARNeg cells in human prostate cancer bone metastases express Interleukin-1beta (IL-1β) while ARPos cells lack IL-1β, and that the presence of ARNeg cells in a metastatic lesion of the bone permits IL-1β-dependent colonization and growth of ARPos cells in a mouse model of intracardiac injection. The inverse correlation between AR and IL-1β resulted in our pursuit to elucidate the molecular mechanism of this phenomenon. We demonstrate that inhibition of AR activity through ADT or the use of Enzalutamide, a potent AR antagonist, results in a time-dependent increase in IL-1β transcription. We provide evidence that the AR regulates the production of IL-1β mRNA through binding to the promoter. Additionally, we reveal that IL-1β is post-transcriptionally regulated by metastasis suppressing micro-RNAs, giving insight into the pathway of trans-differentiation from an ARPos phenotype to an ARNeg phenotype.