Biomaterial Platforms to Study Cancer Dormancy and Develop Therapeutic Strategies for Breast and Ovarian Cancers

Abstract

In breast and ovarian cancer, the primary source of mortality is metastasis. Even in patients who are thought to be cancer-free after initial treatment, metastatic recurrence after months or years of asymptomatic latency period in patients is common in both cancers. Cancer cells that stay dormant and evade chemotherapy have been thought to underpin the metastatic recurrence, but the underlying mechanisms are unclear thus far. Despite advances in cancer treatment, recurrent metastatic cancer is rarely curable. Thus, preventing metastatic recurrence by preemptively eliminating dormant cancer cells is a key to reduce the mortality in breast and ovarian cancers. To effectively target and destroy dormant cancer cells evading chemotherapy, well-established experimental platforms for a better understanding of their unique biological characteristics as well as development of novel therapeutic strategies are required. The work presented in this dissertation aims to provide facile in vitro and in vivo experimental platforms that enable the investigation of cancer dormancy in breast and ovarian cancers as well as to develop a novel therapeutic alternative to chemotherapy to destroy ovarian cancer cells, as current therapeutic options for ovarian cancer are much more limited than for breast cancer. In the first study, an in vitro platform that stably induced dormant state in breast and ovarian cancer cells was developed using cobalt chloride (CoCl2), a hypoxia mimetic agent. Hypoxia has been identified as a microenvironmental niche that harbors dormant cancer cells in many types of cancer, but its role in cancer dormancy has been poorly understood due to the lack of models that stably induce and maintain hypoxia and dormancy. CoCl2 created a robust hypoxia-mimicking microenvironment where breast and ovarian cancer cells could remain in a dormant state for molecular characterization. This platform enables investigation of poorly-understood molecular mechanisms underlying cancer dormancy under hypoxia in both cancers. To investigate hypoxic regulation of cancer dormancy in a more physiologically relevant context, an in vivo platform combining CoCl2 with biomaterial scaffolds composed of poly(lactide-co-glycolide; PLG) was also developed. The PLG scaffolds that release CoCl2 established an in vivo hypoxic niche that can recruit disseminating cancer cells, enabling investigation of how a hypoxic niche harbors dormant cancer cells at metastatic sites. Though the in vivo platform was tested with a previously established breast cancer metastasis model, this platform could be also used to study ovarian cancer dormancy within a hypoxic niche in the body. Lastly, we present a novel biomaterial-based therapeutic strategy to destroy metastatic ovarian cancer cells via sonodynamic therapy. Conventional chemotherapy, which mainly targets rapidly proliferating cancer cells, has been ineffective for non- or slow-proliferating dormant cancer cells. To address this issue, an alternative therapeutic strategy was developed using graphene nanoribbons (GNR) functionalized with a sonosensitizer, chlorin e6 (Ce6). This biomaterial-based approach effectively destroyed ovarian cancer cells through sonodynamic ablation and could be used to reduce the metastatic recurrence resulting from the cancer cells evading chemotherapy. Altogether, the experimental platforms and therapeutic strategy established in this dissertation may provide us a better understanding of dormancy in breast and ovarian cancers as well as a new treatment option that can prevent metastatic recurrence.