MDNews - Central Pennsylvania

advances in chemotherapy, radiation and immunotherapy, the five-year relative survival rate for localized prostate cancer is close to 100%. But for men who have cancers that do metastasize to distant parts of the body, 70% are likely to die within five years. In fact, prostate cancer is the second leading cancer-related cause of death in men and kills more than 33,000 people in the U.S. every year. "If we could know in advance which patients will develop metastases, we could start treatments earlier and treat the cancer more aggressively," says Cory Abate-Shen, PhD, the study's senior author and Chair of the Department of Molecular Pharmacolog y and Therapeutics, the Michael and Stella Chernow Professor of Urologic Sciences, and professor of pathology and cell biology at Columbia University Vagelos College of Physicians and Surgeons. "The problem is that with existing tests, it's hard to know which cancers are which," adds Arriaga. "We miss a lot of aggressive cancers that should have been treated earlier, and we overtreat some slow-growing cancers that probably would not have spread." FROM MICE TO MEN Arriaga and his team at the Abate-Shen Lab sta r ted with mice, developing a unique model in which the cancer spon- taneously metastasizes to bone in the research animals. "This allowed controlled and compre- hensive studies of bone metastasis that had not been possible before," Arriaga says. "These studies showed bone metas- tases from these mice were molecularly conserved with human cancer." The researchers found that bone metas- tases have a different molecular profile than that of primary tumor, including specific patterns of subclonal branch- ing, and that variations in the MYC and R AS genes, a long with 14 others, can activate metastases in prostate cancer in mice. After testing the now-ca lled M ETA-16 gene sig nat u re i n hu ma n samples, they found it reliably predicted which patients had cancer that would metastasize— and how long that cancer would take to metastasize. It also pre- dicted which patients' cancers would respond to a nti-a ndrogen therapy, a therapy used to suppress the hormone that often encourages tumor growth. "By identifying genes enriched in bone metastasis, we can begin to understand what are the molecular processes respon- sible for bone metastasis, and therefore how to design better therapies to prevent their occurrence or treat them once they occur," Arriaga says. HOW THE RESEARCH CAN HELP TREATMENT Recent innovations in cancer treatment have brought striking improvements in the treatment of metastatic prostate can- cer. Anti-androgen therapy in particular can benefit a certain subset of patients, but it's not always easy to determine who those patients are. "One current cha llenge in patients with localized prostate cancer is deciding whether to administer certain treatments or not," Arriaga says. "These treatments may have considerable side effects, so we want to treat only the subset of patients that will likely benefit, while sparing the rest from unnecessary side effects." If further research bears out what the team has learned so far, it could help identify which patients are more likely to respond to a particular therapy and allow better tailoring of treatments to individua l patients, an approach that researchers hope will improve overall outcomes. As Arriaga says, "Our gene signature now provides a new tool that can be used to guide precision medicine for … androgen receptor signaling inhibitors." WHAT'S NEXT Fur t her clinica l tria ls a re pla nned, although the pandemic has slightly slowed things down. "The next step is to design trials that could tell us whether the use of our sig- nature can actually be of use to clinicians and bring benefits to patients," Arriaga says. "We hope our studies can help reduce mortality rates and spur the development of novel therapies." The team also is interested in finding out whether this type of sequencing might be replicable for other types of metastatic cancer and could thus could hold multifold treatment potential. "As other cancers metastasize to bone, it would be ver y interesting to study whether our signature can be applied in such contexts as well," Arriaga says. n " By identifying genes enriched in bone metastasis, we can begin to understand what are the molecular processes responsible for bone metastasis, and therefore how to design better therapies to prevent their occurrence or treat them once they occur." — JUAN ARRIAGA, PHD, POSTDOCTORAL RESEARCH SCIENTIST AT COLUMBIA UNIVERSITY VAGELOS COLLEGE OF PHYSICIANS AND SURGEONS AND THE SCHOOL'S ABATE-SHEN LAB M D N E W S . C O M /// M D N E W S C E N T R A l P E N N S y lVA N I A ■ 2 0 21 1 5

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