Our studies during the previous funding period focused on understanding the relationship between hypoxia and stem like breast cancer cell (SBCC) markers such as CD44, and understanding the effect of targeting hypoxia and choline metabolism on their expression. These studies identified hypoxia as a regulator of CD44. Hypoxia inducible factor (HIF) silencing reduced, but did not eliminate, CD44 expression in primary and metastatic tumors, and decreased metastasis from these tumors in a CD44 expression dependent manner. In human breast cancers, we observed strong expression of CD44 in breast cancer cells and in cancer associated fibroblasts (CAFs) that were closely associated with straight long collagen 1 (Col1) fibers that are typical of an invasive metastatic extracellular matrix (ECM) phenotype. Our data highlight the importance of understanding the functional roles of CD44 in shaping the ECM, including Col1 fibers, in choline metabolism, vascularization, and in invasion and metastasis. CD44 also presents an important target in triple negative breast cancer (TNBC) where chemotherapy is currently the only recourse for treatment. Preliminary studies using antibody based phototherapy (PT) to eliminate CD44 expressing cancer cells showed a dramatic reduction of tumor volume in a CD44 expressing triple negative MDA-MB-231 human breast cancer xenograft. These data have shaped the new directions of this renewal application.
In Aim 1 we will understand the role of CD44 in modifying Col1 fiber patterns, attracting CAFs, modifying choline metabolism, altering vascularization and hypoxia, and decreasing invasion and metastasis in MDA-MB-231, SUM-159 and SUM-149 TNBC xenografts expressing short hair pin RNA (shRNA) to downregulate CD44. The applications of molecular and functional imaging to expand our understanding of CD44 as a molecule that is known to influence survival and treatment outcome are essential for improving treatment strategies for TNBC as well as other cancers where CD44 is associated with a stem cell like phenotype.
In Aim 2 we will develop and optimize antibody based PT of CD44 expressing cancer cells and CAFs in MDA-MB-231, SUM-159 and SUM-149 TNBC xenografts and the MMTV- PyV MT GEMM (genetically engineered mouse model) of breast cancer, and determine the effect on tumor growth, metastasis, CAFs, Col1 fiber patterns, choline metabolism and vascularization. As part of this aim we will develop catheter and endoscopy strategies to detect and treat CD44 expressing tumors for future human applications of PT. Despite an initial response to chemotherapy, TNBCs relapse, display refractory drug- resistance, and metastasize earlier than other subtypes. There is an urgent unmet need for effective precision medicine of TNBC. PT using a phthalocyanine dye such as IR700 conjugated to CD44 antibody provides a safe and specific strategy to eliminate CD44 expressing cancer cells and CAFs with a clear translational path.
The applications of molecular and functional imaging to expand our understanding of CD44 as a molecule that is known to influence survival and treatment outcome are essential for improving treatment strategies for triple negative breast cancer as well as several cancers where CD44 is associated with a stem cell like phenotype. Phototherapy using a phthalocyanine dye such as IR700 conjugated to CD44 antibody provides a safe and specific strategy to eliminate CD44 expressing cancer cells and CAFs with a clear path for human applications in the intraoperative setting, to eliminate any residual CD44 expressing cells in the tumor bed to minimize recurrence, or in the metastatic disease setting, with endoscopic or catheter based approaches, for lesion specific treatments.
| Shah, Tariq; Krishnamachary, Balaji; Wildes, Flonne et al. (2018) Molecular causes of elevated phosphoethanolamine in breast and pancreatic cancer cells. NMR Biomed 31:e3936 |
| Goggins, Eibhlin; Kakkad, Samata; Mironchik, Yelena et al. (2018) Hypoxia Inducible Factors Modify Collagen I Fibers in MDA-MB-231 Triple Negative Breast Cancer Xenografts. Neoplasia 20:131-139 |
| Bharti, Santosh K; Mironchik, Yelena; Wildes, Flonne et al. (2018) Metabolic consequences of HIF silencing in a triple negative human breast cancer xenograft. Oncotarget 9:15326-15339 |
| Bhujwalla, Zaver M; Kakkad, Samata; Chen, Zhihang et al. (2018) Theranostics and metabolotheranostics for precision medicine in oncology. J Magn Reson 291:141-151 |
| Chen, Zhihang; Krishnamachary, Balaji; Penet, Marie-France et al. (2018) Acid-degradable Dextran as an Image Guided siRNA Carrier for COX-2 Downregulation. Theranostics 8:1-12 |
| Penet, Marie-France; Kakkad, Samata; Pathak, Arvind P et al. (2017) Structure and Function of a Prostate Cancer Dissemination-Permissive Extracellular Matrix. Clin Cancer Res 23:2245-2254 |
| Bharti, Santosh K; Wildes, Flonné; Hung, Chien-Fu et al. (2017) Metabolomic characterization of experimental ovarian cancer ascitic fluid. Metabolomics 13: |
| Krishnamachary, Balaji; Stasinopoulos, Ioannis; Kakkad, Samata et al. (2017) Breast cancer cell cyclooxygenase-2 expression alters extracellular matrix structure and function and numbers of cancer associated fibroblasts. Oncotarget 8:17981-17994 |
| Mori, Noriko; Wildes, Flonné; Takagi, Tomoyo et al. (2016) The Tumor Microenvironment Modulates Choline and Lipid Metabolism. Front Oncol 6:262 |
| Dore-Savard, Louis; Lee, Esak; Kakkad, Samata et al. (2016) The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts. Sci Rep 6:39460 |
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