Targeting Common but Complex Proteoglycans on Breast Cancer Cells and Stem Cells Using Evolutionary Refined Malaria Proteins

Breast cancer is responsible for ~40,000 deaths in the United States per year. A major goal of breast cancer research is to identify targets for diagnostic, prognostic, and therapeutic use. Traditionally, such targets include proteins expressed on the surface of breast cancer cells, and blockade of those proteins by antibodies or small molecule antagonists has proven effective for treatment of several types of human breast cancer. Regrettably, some types of breast cancer can develop resistance to the current treatments, resulting in disease recurrence and metastatic spread. To resolve this therapeutic resistance, novel ideas and strategies that explore alternative targeting opportunities are required. We intend to investigate such a novel approach by taking advantage of a specific sugar-binding protein discovered in the malaria parasite Plasmodium falciparum.

In pregnant women, parasite-infected red blood cells express a protein that binds a distinct sugar structure present only on a subgroup of proteins in the placenta. This refined binding system enables the parasite to evade clearance, thereby causing pregnancy-associated malaria outbreaks in epidemic regions of the world. We have recently discovered that human breast cancer cells express this same carbohydrate structure on the human placental cells. The carbohydrate structure enables the breast cancer cells to migrate and invade surrounding normal tissue and plays a role in metastatic spread of the primary breast tumor. Our purified malarial protein can efficiently bind patient-derived breast tumor tissue and several subtypes of human breast cancer cells with high strengths, inhibiting their sugar structure-dependent motility. This raises the intriguing possibility that we can use this naturally refined parasite-host interaction unit as a tool to specifically bind human breast cancer cells and inhibit their metastatic potential. Furthermore, as the malarial protein binds strongly to patient-derived breast cancer tissue, this protein could be used to differentiate between specific subtypes of human breast cancer to improve the diagnostic process in clinical settings.

In summary, we propose to combine our individual expertise in parasitology (Dr. Salanti) and oncology (Dr. Daugaard and Dr. Sorensen) to investigate the potential of exploiting the interaction between the malarial protein and the breast cancer sugar structure as a novel approach to inhibit metastatic growth of different subtypes of recurrence-prone human breast cancer. In addition, we will evaluate the potential of using the presence of this protein-sugar interaction to diagnose and predict the outcome of different subtypes of human breast cancer. These studies could potentially lead to the identification and development of a completely novel class of therapeutic anti-cancer compounds for the benefit of breast cancer patients worldwide.