T.J. Martell Foundation-supported scientists have identified a “master regulator” gene driving aggressiveness in prostate cancer.
Scientists at Mount Sinai Hospital in New York, with the support of the T.J. Martell Foundation, have discovered a gene that acts as a switch and activates the aggressiveness of tumor cells. The discovery could have a major impact on the development of treatments for prostate cancer.
Prostate cancer is the most common tumor and one of the leading causes of cancer death in men. In about 10-15% of patients prostate cancer has an aggressive disease course characterized by the appearance of tumors in distant organs (metastasis) and the acquisition of resistance to anticancer drugs, which contributes to the death of most patients with prostate cancer.
The study, led by Dr. Josep Domingo-Domenech published and highlighted in the cover of the prestigious scientific journal Cancer Cell, describes a mechanism by which prostate cancer cells become aggressive and survive standard treatment. The key is a gene called GATA2, which encodes a transcription factor capable of reprogramming and activating aggressive cells through activation of multiple signaling pathways.
Using computational biology techniques that integrate genetic information from prostate cancer cells in humans and experimental models it has been possible to identify the master regulator gene GATA2. It was observed that experimental prostate cancer tumor cells with high levels of GATA2 initiated aggressive tumors that were resistant to chemotherapy. GATA2 gene acts as a master gene, controlling the activation and expression of many other genes. It activates other genes, putting them to work invading healthy tissue and initiating metastasis. Other genes are set to activate survival pathways that help initiate tumors and make cells resistant to anticancer drugs. This is the case for the gene coding the growth factor IGF2, which is activated directly by GATA2 triggering a signaling cascade that increases tumor cell survival under adverse conditions.
Importantly the discovery of the master gene, GATA2, that regulates expression of IGF2 led to the identification of a new therapeutic strategy for patients with prostate cancer. The new treatment strategy combines chemotherapy with IGF2 pathway inhibitors which improves the results of chemotherapy and allows more durable responses. Dr. Domingo- Domenech explains, ‘the combination of chemotherapy with IGF2 pathway inhibitors helps enhance the antitumor effect of chemotherapy and was well tolerated in animal models. Now we are looking forward to translate these studies into patients.”
“This important finding is a clear example of the excellent science with important clinical implications for cancer patients that the T.J. Martell Foundation is currently funding,” says Dr. James Holland, the founding research scientist for the T.J. Martell Foundation. The support that the T.J. Martell Foundation has given Dr. Domingo- Domenech during the last years is helping enormously to uncover new therapeutic targets against this devastating disease.