This project is designed to allow independent experts in the development and/or application of in vitro breast cancer diagnostic tests, Drs. Badve (breast pathologist) and Sledge (breast oncologist), to evaluate INTICA's candidate anti-DEspR mAbs to develop the preliminary materials and methods for a commercially viable companion diagnostic test. DEspR, the dual endothelin-1 (ET-1)/vascular endothelial growth factor (VEGF) signal peptide (VEGFsp) receptor is a novel, alternate pro-angiogenic/pro-metastatic cancer target and pathway involved in cancer resistance to anti-angiogenesis therapies. DEspR is expressed on tumor vascular endothelial cells (TVECs), tumor cells (TCs) and cancer stem cells (CSCs) in """"""""triple-negative"""""""" (TNBC;estrogen, progesterone and Her2 receptor-negative) breast cancer (BCa), pancreatic adenocarcinoma (PCa) and glioblastoma multiforme (GBM) primary tumors and respective cell lines (MDA- MB-468, Panc-1, U87). INTICA is developing INTI-1, an Anti-DEspR Therapeutic mAb for use against DEspR+ cancers, such as TNBC, PCa and GBM, where anti-angiogenic therapies are ineffective despite the presence of VEGFRs on TVECs and some TCs. Anti-DEspR therapy in vitro prevents HUVEC angiogenesis, TC invasiveness and CSC tumorsphere formation and promotes CSC anoikis (apoptosis), and in vivo inhibits DEspR+ spontaneous tumor and CSC xenograft growth. INTICA is also developing a Companion Diagnostic (CDx) mAb as a commercial in vitro CDx device to stratify DEspR+ tumors for patient response to INTI-1.
The Specific Aims of this project are: 1) to manufacture candidate CDx mAbs;2) to survey human primary BCa/TNBC tumors and tumor microarrays (TMAs) for DEspR by immunohistochemical staining (IHCS) with candidate CDx mAbs, to: a) develop IHCS methods, b) correlate DEspR expression on TVECs, TCs and CSCs with tumor characteristics (e.g., grade, malignancy, invasiveness, vascularity), c) correlate DEspR expression with Oncotype DX"""""""" recurrence scores and survival analysis, and d) select the preferred CDx mAb;3) to design a preliminary CDx IHCS scoring system to stratify DEspR+ tumors and identify BCa/TNBC cancer patients likely to benefit (or not benefit) from anti- DEspR therapy with INTI-1;and 4) to use these CDx methods to select human TNBC cell lines with varying DEspR expression for use in xenograft models to test INTI-1. The resulting CDx test will be used in Phase 1 clinical trials of INTI-1. Key Words. Cancer, TNBC, DEspR, INTI-1, companion diagnostic, anti-angiogenic, anti-metastatic, cancer stem cells Brief Summary. The discovery of DEspR, a novel target on cancer stem cells, tumor cells and tumor blood vessels, and pathway involved in cancer metastasis, recurrence and angiogenesis, provides a new treatment paradigm. Combined use of anti-DEspR companion diagnostic and therapeutic mAbs has the potential to alter oncology clinical practice, particularly in BCa/TNBC, as an addition to or advantage over existing treatments.
The discovery of DEspR, a novel target on cancer stem cells, tumor cells and tumor blood vessels, and a pathway involved in cancer angiogenesis, metastasis and recurrence provides a new cancer treatment paradigm. This project is designed to allow independent experts in the development and/or application of in vitro breast cancer diagnostic tests, Drs. Badve (breast pathologist) and Sledge (breast oncologist), to evaluate INTICA's candidate anti-DEspR mAbs to develop the preliminary materials and methods for a commercially viable companion diagnostic test. This project explores the combined use of an anti-DEspR companion diagnostic monoclonal antibody (mAb) to screen and stratify DEspR+ breast cancer tumors to identify patients likely to benefit (or not benefit) from anti-DEspR therapy with a therapeutic mAb, INTI-1. As envisioned, this approach has the potential to alter oncology clinical practice, particularly in triple-negative breast cancer (TNBC), as an addition to or advantage over existing treatments.
