TMC PULSE

t m c » p u l s e | n o v e m b e r 2 0 1 7 10 Tricking Cancer Houston Methodist researchers receive nearly $16 million from the U.S. Department of Defense to battle metastatic breast cancer B y S h a n l e y C h i e n A multidisciplinary team of researchers and clinicians at Houston Methodist received nearly $16 million from the U.S. Department of Defense's Breast Cancer Research Program to fast-track a revolutionary new drug that could potentially provide a long-term cure for metastatic triple negative breast cancer (TNBC). Nanoscientist Mauro Ferrari, Ph.D., president and CEO of the Houston Methodist Research Institute, and his team of biologists, clinicians, pharma- cologists and engineers, have spent seven years researching and develop- ing a nanoparticle drug—an injectable nanoparticle generator polymeric doxorubicin, known as iNPG-pDox— that tricks metastatic growths into producing tumor-killing agents. In preclinical cases, iNPG-pDox cured an unprecedented 50 percent of TNBC with metastases to the lung and liver in mice models. If these results successfully translate to humans, Ferrari explained, that would be equiva- lent to approximately 24 years of long- term, disease-free survival. Although the other half of the cases were not cured, the drug was still able to shrink metastatic tumors, allowing the mice to live three times longer. "By having an impact on liver and lung, we could literally save the major- ity of metastatic patients. Nobody has ever cured metastatic disease, so this is an exciting opportunity," Ferrari said. A painful journey Breast cancer is the second most common cancer in women, behind skin cancers. The American Cancer Society estimates approximately 252,710 new invasive breast cancer cases and about 40,610 deaths each year. Because of increased awareness, early detection and more advanced therapies, the survival rates for female breast cancer patients steadily improved between 1989 and 2015. Stage 0 or stage I breast cancer patients have nearly a 100 percent 5-year survival rate. Stage II patients have a 93 per- cent 5-year survival rate. And stage III patients have a 72 percent 5-year survival rate. However, once the cancer has metastasized to other parts of body (such as the lungs, liver and brain), the 5-year survival rate drops to 22 percent. Chances of survival are much bleaker for patients with metastatic TNBC, a more aggressive form of breast cancer that has a higher recurrence rate after treatment. TNBC is called "triple negative" because it tests negative for estrogen receptors, progesterone recep- tors and human epidermal growth factor receptor 2. These receptors are responsi- ble for the growth of most breast cancers and are often what doctors target to treat the cancer. Because they are not present in TNBC patients, treating their cancer is akin to taking a shot in the dark. "It is a particularly painful journey for patients," said Jenny Chang, M.D., director of the Houston Methodist Cancer Center. "For a long time now, we've been trying to find out what really drives triple negative breast cancer. We've had some successes, but by and large, even today, the only treatment for triple negative breast cancer is chemo- therapy. Once it's metastatic, it's still largely incurable." Even immunotherapy drugs, although promising, are not the holy grail for metastatic TNBC patients. "If they work, they will work very well. They can significantly and dramat- ically extend a patient's life, but they are only helping a very small number of patients," said Haifa Shen, M.D., Ph.D., a lead scientist at Houston Methodist in the department of medicine. "Now, with iNPG-pDox, we are talking about the vast majority of patients who are still not being properly taken care of. There's a major task ahead of us in cancer treatment." As metastatic tumors grow and evolve, the layers of biological barriers (circulation, tumor microenvironment, cells and organelles) that direct the traffic of cells, molecules, nutrients and metabolites in the body mutate. This changes how the barriers function and redirects chemotherapeutics away from normal pathways, weakening the potency and efficacy of the drugs that do make it to the tumor site. Because the chemotherapeutics cannot com- pletely wipe out the cancer in this fashion, tumor cells repopulate and develop a therapeutic resistance. "It turns out that [getting through the barriers] requires multiple actions, The reason we got to this point is because we were able to observe 25 years of failures. Failure is feedback. If you can find a way not to get too depressed about all of that feedback, then you can learn. — MAURO FERRARI, PH.D. President and CEO of the Houston Methodist Research Institute Haifu Shen, M.D., Ph.D., a lead scientist at Houston Methodist, with Mauro Ferrari, Ph.D., president and CEO of the Houston Methodist Research Institute.

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