A Highly Superior and Selective Cancer Immunotherapy-Based Approach for Triple-Negative Breast Cancers
Abstract
Mortality rates in triple-negative breast cancer (TNBC) patients have remained relatively unchanged in the last two decades. Across the United States, approximately 50,000 women die every year due to the TNBCs, one of the most lethal among all breast cancer types. Although overall breast cancer incidence rates are higher among white women than African Americans, mortality rates are higher among African Americans. The latter is also evident in the US military, where 30.7% of active-duty enlisted women are African American (51.7% being white). It is debatable whether survival differences are due to disparities in access to healthcare treatment. On the contrary, it is quite clear that aggressive TNBCs disproportionally affect young women of African origin. Therefore, a large number of hardworking women minorities in US military die due to TNBCs every year. Besides, the TNBCs diagnosis could potentially set up new, or worsen preexisting post-traumatic stress disorder (PTSD) among military families. Additionally, the 5-year survival rates tend to be lower for TNBCs than for other forms of breast cancers. For patients that are diagnosed with advance stages of the disease (III and IV), >80% only survive less than 1 year. Since targeted therapies are not available, the treatment options for TNBCs patients include repetitive surgery followed by chemotherapy. While many patients respond to these interventions, the disease prognosis is very poor, and up to 85% of recurrent cancer patients develop chemoresistance and eventually die. It is therefore critical to design, investigate, and test novel multifaceted biological therapies with the potential to selectively slow down the TNBCs by exploiting inherent cancer properties that are essential for disease progression. A mono-specific antibody is a biological agent that can selectively bind and oppose the function of a single cancer activating protein (antigen). Similarly, a bi-specific antibody can bind to two different cancer specific proteins and has the inherent properties to block two cancer-causing cellular pathways at the same time. Bi-specific antibodies have proved clinically effective for acute lymphocytic leukemia (ALL), a blood cancer that similar to TNBCs encounters very frequent chemoresistance and extremely low survival rates. Approximately 30% of relapsed ALL patients have received remission due to this novel bi-specific antibody that bridges the body’s immune killer cells next to a blood cancer cells, to selectively destroy them. Here, we propose that similarly constructed dual-operating antibodies that induce directed cell-death selectively in TNBC tissue, by making use of cancer enriched proteins, will have a direct pharmacological effect on the disease. Hence, we put forward to investigate and test a novel dual-specificity antibody that targets: (1) TNBC-enriched protein called folate receptor alpha-1 (FOLR1) and (2) TNBC epithelial tissue responsive cell-death activating receptor called DR5 or TRAIL-R2. FOLR1 is overexpressed (multiple-fold higher than normal breast) in >80% of TNBC subtypes and will function to anchor the bi-specific antibody molecule selectively in the cancer tissue. Due to multiple (four total) binding sites in bi-specific molecule, the second components of this dual affinity molecule (that activate DR5/TRAIL-R2 signaling) will be retained in the tumor tissue to engage and instigate cell death pathway selectively in FOLR1+ (TNBC) cell populations. This combinatorial targeting approach based on preliminary data (that we have generated) offers a promising path for selective and effective disease treatment, especially for highly aggressive chemoresistant TNBC patients. Importantly, since the cytotoxicity of antibody is highly dependent on TNBC overexpressed anchor protein, the toxicity-associated risks will be significantly reduced in other tissues. Thus, the proposed studies are highly focused to test safety, selectivity, and e
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810048
Entities
People
- Jogender Tushir-singh
Organizations
- United States Army
- University of Virginia