Description:

Successful management of melanoma will require eliminating both the primary cancer as well as its spread. The survival of melanoma patients reduces significantly if the cancer spreads to the brain. Five-year patient survival after melanoma spreads to brain is only 5%. The key contributor for growth of melanoma is changes in a protein called BRAF. Similarly, the major factor that influences melanoma to spread to the brain is a protein called AKT. To reduce cancer spread, a number of novel treatments are currently being evaluated. Our hypothesis is that targeting the AKT and BRAF pathways will reduce both cancer as well as its spread to the brain, by increasing an important protein, called p53. One such treatment strategy to achieve this is inhibition of AKT and WEE1, WEE1 being a downstream protein in the BRAF pathway. We have previously shown that targeting AKT and WEE1 is superior to targeting either of the proteins alone in reducing melanoma development. Therefore, the central hypothesis of this project is to test the effect of p53-modulation on melanoma metastasis to the brain. The project will be accomplished by first identifying the best strategy to target the p53 pathway using genetic modifications and drugs. The best identified strategy will be tested for its effect on the p53 pathway and regulation of growth of melanoma cells. Finally, this strategy will be evaluated to decrease melanoma growth and its spread to brains in a mouse model. This discovery would identify unique approaches to overcome melanoma brain metastasis thereby improving the survival of patients.

Description:

Cancer immunotherapy (CI) drugs activate our own immune system to directly kill cancer cells. These drugs have revolutionized how we treat many cancers including melanoma. However, not all patients respond equally to CI treatment, and we still do not fully understand why. Surprisingly, microorganisms in our gastrointestinal tract known collectively as the gut microbiota may be necessary for effective CI treatment. Melanoma, lung, and kidney cancer patients who responded to CI drugs contained a higher abundance of specific bacteria including Enterococci species compared to non-responding patients. These results suggest that individual bacterial species in the gut may improve CI therapy. Nevertheless, how this occurs is still unclear. In parallel, our laboratory has found that one Enterococcus species, Enterococcus faecium (Efm), can protect against infection by activating the immune system. Efm produces SagA, an enzyme that breaks down the bacterial cell wall to produce small molecules that stimulate innate immunity via the sensor Nod2. Based on these results, I hypothesize that Enterococcus species can also improve CI drug effectiveness through the direct activation of host immunity via a similar mechanism. To test this, I will first examine how colonization of the GI tract with Enterococci can directly change the growth of melanoma in mice and alter immune cell activation within the tumor during CI treatment. To decipher how Enterococci can alter drug response, I will then test whether the SagA enzyme and the resulting small molecule it produces are sufficient to improve CI drug effectiveness against melanoma. Finally, I will determine whether Enterococci-mediated melanoma suppression also requires the host sensor Nod2. Together, these experiments will provide direct evidence for how individual species of commensal bacteria can activate the host immune system during immunotherapy treatment of melanoma. Results from this proposal may allow us to predict how well patients will respond to CI drugs by detecting the presence of SagA-expressing Enterococci bacteria in their GI tract. Moreover, the microbial and host components I identify may provide new ways to improve clinically approved CI drugs via new probiotic or small molecule combination therapies. 

Description:

Metastasis is the main cause of melanoma death. Current treatments mostly fail to cure metastasis. It is of common knowledge that disseminated cancer cells (DCCs) are the seeds of future metastasis. Once these DCCs arrive to secondary organs they undergo a dormancy program that involves cell cycle arrest or quiescence. DCCs could remain in this state for months to almost decades and they are able to survive current treatments. The reason is because most current therapies target anti-proliferative cells, thus dormant DCCs remain unaffected. Eventually these DCCs reactivate and they start forming metastases. After the detection of a melanoma lesion and treatment, patients enter a phase of remission in where no symptoms of disease are detectable and one can say that patients are “cured.” However, the majority of these patients will develop metastasis that will arise from DCCs. Clinical analyses suggest that dissemination of DCCs happens very early during melanoma progression. Therefore, understanding how DCCs enter dormancy and what makes them reactivate to form metastasis is of extreme significance to design novel treatments. We designed a protocol to reprogram tumor cells into long-term dormancy by combining an inhibitor of methylation plus retinoic acid. These reprogrammed dormant cells upregulated a transcription factor named NR2F1, which was responsible for the dormancy phase. We validated that NR2F1 could be used as a biomarker to determine dormancy status of DCCs in breast and prostate cancer patients. Moreover, the above-mentioned protocol is now part of a clinical trial to treat advanced cancer patients. In addition, previous results showed that patients with melanoma positive for a secreted factor named Midkine relapsed earlier than those patients that were negative for Midkine. Interestingly, when we blocked Midkine the levels of NR2F1 factor were upregulated reinforcing dormancy of DCCs and reducing metastasis formation. Thus, we propose a therapeutic strategy to keep those DCCs in a dormancy phase by blocking the reactivation signal (midkine) and inducing dormancy signals (NR2F1). We believe this treatment could stop DCCs from forming life-threatening metastases.