Tech Highlights

Exploiting the Estrogen Receptor Beta and TP53 Interaction As A Novel Therapeutic Strategy For Cancer

Gokul Das, PhD

Inventor: Gokul Das, PhD

Currently, available targeted therapies for aggressive triple negative breast cancers (TNBC) are inadequate. These cancers are unresponsive to hormone modulation, and with the long-term ineffectiveness of cytotoxic chemotherapy, treatment options for patients are typically limited to surgical resection, radiation and highly toxic broad-spectrum chemotherapies. Accordingly, there is an urgent need to discover new therapeutic targets and strategies for treating TNBC.

The present technology addresses this need by first stratifying TNBC patients based on the mutagenic state of the tumor suppressor gene product, p53, i.e., the genomic gatekeeper, in combination with the expression level of estrogen receptor beta, ERb. In this respect, TNBC patients possessing a mutated p53 protein phenotype, while also expressing low levels of ERb, are selected for receiving a combination of tamoxifen and doxorubicin.

Specifically, when administered in combination with tamoxifen, doxorubicin can be administered at much lower doses than if provided to the patient as a monotherapy. Consequently, TNBC patients now have increased access to chemotherapies that may have been previously far too toxic to administer alone.


Treatment of HER2-Positive Cancers with Prolidase

Breast cancer tumors that possess the human epidermal growth factor receptor-2 (HER-2) are called HER-2 positive cancers. These cancers can be invasive and spread rapidly if not detected early and treated with efficacious drugs. The HER-2 receptor, moreover, is the major target in 20-30% of all human breast cancers. Overexpression, amplification and activating-point mutations of the HER-2 family of receptors promotes the development of cancer cells, is associated with an aggressive clinical phenotype and remains a strong indicator of poor disease prognosis.

Drug resistance to current HER-2 inhibitors, such as the frontline therapy Herceptin®, is one of the major unresolved clinical problems that oncologists face today. In fact, approximately half of all breast cancer patients show primary or secondary resistance to Herceptin, among other treatments, for HER-2 positive breast cancer.

Human peptidase D (PEPD), i.e., prolidase, is a native enzyme found in all human cells, which has been shown to strongly inhibit HER-2 in breast cancer cells. As such, insofar as HER-2 remains overexpressed in drug-resistant breast cancer cells, the present technology is directed towards an enzymatically inactive, recombinant form of PEPD that is able to overcome Herceptin resistance via its interaction with the HER-2 receptor.


Targeting Glucose-Stimulated Phosphohistidine Signaling in Esophageal Cancer

Cancers that do not respond to growth factor inhibition therapy, e.g., tyrosine kinase inhibitors (TKIs), pose significant challenges for clinical oncologists. One such cancer is esophageal squamous cell carcinoma (ESCC). Although these tumors are genetically disparate, they all share a common metabolic weakness, i.e., their proliferation requires glucose.  ESCC tumors, in this regard, are able to reprogram glucose metabolism to promote tumor growth in the absence of cellular growth factors. This reprogramming is achieved through the activity of focal adhesion kinase (FAK).

The present technology entails small molecule inhibitors that specifically interrupt the glucose-induced FAK signaling that drives ESCC growth. By directly binding to a critical pocket on FAK, these small molecules prevent glucose-stimulated tumor progression in patients possessing drug-resistant malignancies, while not impacting glucose uptake or metabolism in normal cells. Accordingly, this technology portends an innovative way to treat refractory ESCC.