Development of methods, assays, and kits for measuring expression levels of the biomarker Sema7a to determine a cancer’s metastatic potential and tumor aggressiveness and response to cancer therapy. The technology also includes proposed methods for inhibiting cancer cell growth and metastasis with a Sema7A inhibitor.
In the US, cancer is responsible for 25% of all deaths. Death from cancer is primarily due to metastasis of cancer cells to other organs followed by secondary tumor formation throughout the body. Breast cancer is the second most common cause of cancer mortality among women with approximately 40,000 women and 480 men newly affected each year. Despite improved treatment options, breast cancer remains a devastating illness. Therefore, there is a critical need for new predictive and diagnostic assays and treatments for breast and other solid tumor cancers.
The inventors previously reported that Sema7A expression was increased in human breast tumor tissue and breast cancer stem cells (from untreated breast cancer patients), but minimally expressed in adjacent normal tissue. In vivo studies demonstrated that Sema7A gene expression and its products correlate with tumor aggressiveness, influencing tumor growth, metastasis and survival. Specifically, Sema7A promotes monocyte chemotaxis and induces them to produce pro-inflammatory and pro-angiogenic mediators to support tumor growth. It is well-established that tumor-associated macrophages (TAMs) are the most influential among cell types in the tumor microenvironment for tumor progression. Breast cancer in particular is characterized as having a large population of TAMs and there are well documented mechanisms by which TAMs interact and influence surrounding tumor cells.
This technology proposes a diagnostic method to determine the potential for breast cancer metastasis and tumor aggressiveness and serves as a tool to make decisions on proper management and treatment of disease, allowing for individualized patient care. The methods, assays, and kits can be used independently or in combination with additional diagnostic tests and/or prognostic methods.
The assay includes analyzing expression of Sema7A in a biological sample without metastatic potential from a subject with any type of breast cancer and correlating its expression to a control breast cancer sample with metastatic potential. Previously characterized breast cancers of known metastatic potential will be used as a reference. The expression of Sema7A can be measured at the RNA (by polymerase chain reaction (PCR)) or protein level (quantitative Western analysis, ELISA, in situ fluorescence, and other related techniques) and is linearly proportional to the metastatic potential of breast cancer in the subject. The assay may further include the analysis of one or more other breast cancer markers.
The technology also includes a method for measuring a response to breast cancer therapy in a subject with breast cancer. Expression of Sema7A is measured at baseline before treatment and during a second time point wherein the subject receives the breast cancer therapy. The therapeutic response is calculated by comparing the expression of the samples before and during/after treatment.
Sema7A is a novel therapeutic target to limit tumor growth and metastasis of breast cancer and other solid tumors. The technology also proposes compositions of a Sema7A inhibitor such as anti-Sema7A antibodies, small molecule inhibitors, or gene therapies, all of which reduce the expression/activity of Sema7A and inhibit breast cancer cell growth by inducing cell death and decreasing/preventing metastasis.
Diagnostics are used to support clinical development of drugs, predict disease, and identify patients most likely to respond to specific treatments. Although there are a few companies that are marketing a kit for measuring Sema7A in serum, plasma, tissue homogenates, and other biological fluids (Hoelzel Biotech, US Biological Life Sciences, USCN Life Sciences, and Antibodies Online), its marketed purpose is for research rather than using it as a clinical diagnostic tool. The described use of the invention (not the methodology) is the first of its kind stating its use as a clinical diagnostic tool for predicting cancer behavior and therapeutic response. The inventors are also the first to propose Sema7A as a target for treating breast cancer and possibly other solid tumor types and the technology description encompasses a wide variety of treatment options.
Currently, Sema7A has not been widely described in the context of any cancer except breast cancer and highly invasive malignant glioblastomas and may represent an opportunity for the inventors to be the first to identify other cancers, particularly those having a large population of TAMs, which may have a high level of Sema7A expression representative of tumor growth and metastasis. The market for breast cancer diagnostic tools is quite large and further identification of other cancer types would markedly increase the commercial potential of the proposed invention.
The described invention may also extend beyond identification of tumor aggressiveness and metastatic potential with solid tumor types. Evaluation of Sema7A expression may be used to assess autoimmune disorders, chronic obstructive pulmonary disease, inflammation, psoriasis, wound healing, tissue repair, irritable bowel syndrome, stroke, and atherosclerosis.
The inventors are also the first to propose the use of a Sema7A inhibitor for inhibiting cancer cell growth (e.g. aggressive breast cancer) using a variety of inhibitor types. This is particularly important, as most therapies tend to be effective when used in the early stages of cancer. The described invention presents a treatment option for patients with later stages of cancer (which tend to be limited), when tumor burden and metastasis have already occurred. The role of Sema7A in cancer cell growth and metastasis is currently unclear. As more studies elucidate its role and give supporting evidence to its importance in tumor growth and metastasis, the greater the commercial potential of the proposed invention.
Clinical relevancy Studies
Cell culture assays
In vivo studies
U.S. Patent 20130225656A1 Issued on August 29th, 2013.
Dr. Vijaya Iragavarapu-Charyulu, Ph.D., is an Associate Professor of Biomedical Science at Schmidt College of Medicine. He primary research interests include tumor immunology, the role of semaphorins in breast cancer, the effect of chitinase-3-like-1 molecule in breast cancer progression, chitin and immune modulation to inhibit tumor growth and metastasis, and the effect of nicotine on breast cancer growth and metastasis. She has 18 peer-reviewed publications.
Ramon Garcia-Areas is a doctoral student at Florida Atlantic University in Dr. Vijaya Iragavarapu-Charyulu’s laboratory. He has 7 peer-reviewed publications.
Stephania Libreros is a doctoral student at Florida Atlantic University in Dr. Vijaya Iragavarapu-Charyulu’s laboratory. She has 7 peer-reviewed publications.
Oncology, Diagnostic testing, Drug discovery
BrochureAnalyzing semaphorin7a (Sema7A) levels for assessing cancer metastatic potential and methods of treatment
| Patent Number | US8912159 |
| Patent Status | Issued |
| Issue Date | December 16, 2014 |
