Scientists Identify Drug Target As The First Precision Breast Cancer Therapy

Scientists Identify Drug Target As The First Precision Breast Cancer Therapy

A research team led by scientists at the Cancer Research Institute at Beth Israel Deaconess Medical Center (BIDMC) managed to identify a Pin1 enzyme inhibitor that can block tumor growth in acute promyelocytic leukemia (APL) and triple negative breast cancer. Findings were recently published in Nature Medicine.

Targeted cancer therapies function by blocking one oncogenic pathway in order to stop tumor growth; however, tumors usually regrow due to their capacity to evade therapies. Further, tumors contain cancer stem cells that seem to be responsible for their initiation, drug resistance and metastasis; to eradicate these cancer stem cells might be crucial to achieve remission that can actually last for long periods.

Investigators have found that the vitamin A derivative ATRA (all-trans retinoic acid) is able to block multiple cancer-driving pathways and eliminate cancer stem cells  at the same time through degrading the Pin1 enzyme.

“Pin1 changes protein shape through proline-directed phosphorylation, which is a major control mechanism for disease. Pin1 is a common key regulator in many types of cancer, and as a result, can control over 50 oncogenes and tumor suppressors, many of which are known to also control cancer stem cells,” explained Dr. Kun Ping Lu, co-senior author, who also co-discovered the enzyme back in 1996.

Until now, the inhibition of Pin1 has been made through rational drug design, but despite working in in vitro assays they do not function in in vivo models. In this new approach, scientists decided to identify Pin1 inhibitors by developing a mechanism-based high throughput screen to clear compounds that were targeting active Pin1.

“We had previously identified Pin1 substrate-mimicking peptide inhibitors. We therefore used these as a probe in a competition binding assay and screened approximately 8,200 chemical compounds, including both approved drugs and other known bioactive compounds,” said the researcher.

To improve screening success, a probe that binds very tightly to the Pin1 enzyme active site was chosen. At first, it seemed the screening results had no hits until the cis retinoic acid was spotted, revealing the same chemical formula as all-trans retinoic acid [ATRA], but with another chemical structure.

“While it has been previously shown that ATRA’s ability to degrade the leukemia-causing fusion oncogene PML-RAR causes ATRA to stop the leukemia stem cells that drive APL, the underlying mechanism has remained elusive. Our new high throughput drug screening has revealed the ATRA drug target, unexpectedly showing that ATRA directly binds, inhibits and ultimately degrades active Pin1 selectively in cancer cells. The Pin1-ATRA complex structure suggests that ATRA is trapped in the Pin1 active site by mimicking an unreleasable enzyme substrate. Importantly, ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RAR and treats APL in cell and animal models as well as in human patients,” said Lu.

Researchers found ATRA-induced Pin1 ablation inhibited triple-negative breast cancer growth, turning off several oncogenes and activating some tumor suppressors. These findings can have a major impact in cancer treatment.

“The current ATRA drug has a very short half life of only 45 minutes in humans. We think that a more potent Pin1 inhibitor will be able to target many ‘dream targets,’ that are not currently druggable. ATRA appears to be well tolerated with minimal side effects and offers a promising new approach for targeting a Pin1-dependent common oncogenic mechanism in numerous cancer-driving pathways in cancer and cancer stem cells. This is especially critical for treating aggressive or drug-resistant cancers,” concluded Dr. Lu.

[adrotate group=”3″]

Related --

Related --

Leave a Comment

Your email address will not be published. Required fields are marked *