MYC, MicroRNAs and Metabolism: New Targets for Cancer Therapy

In a recent Dartmouth Medical School Pharmacology and Toxicology seminar, University of California, San Francisco department of medicine associate professor Andrei Goga presented several instances of current research that seeks to take advantage of the cellular cycle of cancer cell to stem its proliferation.

Goga first referred to the MYC gene, a canonical oncogene transcription factor that is overexpressed in variety of cancers, especially those that are associated with poorly differentiated and aggressive tumors.

Goga presented three possible approaches to identity synthetic lethal pathways to target, interrupt, oncogenesis: cell cycle inhibitors, micro-RNAs, and metabolic pathways. The lab’s goal is to identify the pathways and to come up with inhibitors and lead to apoptosis and block tumor formation.

First, Goga presented how targeted therapies could potentially be used for Triple-Negative breast cancer. Already, a number of targeted therapeutic treatments for other breast cancers exist, such as Tamoxifen in estrogen positive cancers and Perceptions and Lapatinib in ERbB2 positive cancers. Triple-Negative Breast Cancer, however, does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu and cannot be treated effectively by hormone-based drugs.

Instead, Goga’s lab attempted to gauge whether MYC activity was an important factor in Triple-Negative Breast Cancer development and studied whether high MYC associated with poor patient outcome and whether MYC expression alter response to conventional chemotherapy.

Through I-SPY, a national, multi-institutional study “to identify biomarkers predictive of response to therapy throughout the treatment cycle for women with stage 3 breast cancer,” researchers found elevated level of MYC expression in Triple Negative tumors. Quantitative protein expression also demonstrated increased protein expression in primary tumors compared to that of receptor positive samples.

To find methods to treat patients who did not respond to traditional therapy, the researchers turned to the discovery that CDK1 inhibition results in synthetic lethality in the context of high MYC expression.

Researchers looked at cell death of breast cancer cells with high MYC induced by CDK inhibitors. After a three-day treatment with purvalanol A and SCH 727965, a potent and selective inhibitor of cyclin-dependent kinases researchers saw not only arrested cell proliferation in tumor cells, but also cell death. This effect was also specifically perceived in Triple-Negative cell lines.

In a study studying the regression of triple-negative breast cancer xenografts on naked mice after CDK inhibitor Treatment, researchers saw a dramatic shrinkage of tumors. Goga surmised that MYC inhibition converge to regulate BIM, which promotes cell apoptosis. Goga concluded that Triple-negative breast cancer cells have elevated levels and activity of MYC and exploiting the synthetic lethal interaction between MYC overexpression and CDK may lead to a viable treatment. Goga stated that his current goal is to extend the work and to address other questions by creating other tumor models in vivo.

Goga also saw miRNA as another potential therapeutic targets for cancer therapy. He first presented evidence of p53 regulation by miR-380 in neuroblastoma, a malignant tumor that develops from nerve tissue in infants and children. Researchers found that over expression miR-380 attenuate expression of normal p53, an important tumor suppressor gene. Researchers demonstrated that the addition of miR-380 antagonists kills cells and showed dramatic growth suppression.

Goga also turned the attention to miR-21, which is “found virtually in every cancer.” The study he presented mainly focused on hepatocellular carcinoma, commonly known as liver cancer and the third leading cause of cancer associated death world wide.  This carcinoma has increased in past decades in developed nations with currently only one approved drug treatment.

Researchers found that miR-21 was upregulated in human and MYC mouse liver models. Members of the Goga lab developed mir-21 antagonists and treated mice HCC models with active oncogenes for 120 days. Half of the mice that were not treated half died within 70-80 days, while many mice that were given the antagonist died only after the treatment supply was depleted. Goga reflected that patients with cirrhosis—scarring of the liver—were more likely to develop HCC, and perhaps a form of miR-21 antagonist could be given preemptively to reduce the risk of liver cancer in humans.

In the final leg of the presentation, Goga suggested that cellular metabolism could potential be linked to effective tumor inhibition. For instance, through a new method of metabolic imaging of tumor models, researchers discovered that elevated alanine level is an indicator of isolated MYC expression in cells, suggesting a new potential biomarker prior to actual tumor formation.

Before wrapping up his presentation, Goga posed a few more questions and outlined his future research goals: Are early and late metabolic changes specific to myc-driven tumors or also present in liver cancers driven by other oncogenes? Is alanine up regulated only a marker of early tumor formation or is it required for tumorigenesis? Can these metabolic imaging approaches be applied to human HCCs?