Identifying Therapy-Resistant Genes in Prostate Cancer Opens Doors

Newitt, Valerie Neff

doi: 10.1097/01.COT.0000515940.87076.a5
News

Ginevra Botta, PhD, spends much of her time exploring the molecular basis of prostate cancer and contributing to breakthrough findings in indentifying resistance mechanisms in the context of drug therapy. After having successfully completed a postdoctoral fellowship funded by the Department of Defense Prostate Cancer Research Program, Botta was honored with a Prostate Cancer Foundation 2016 Young Investigator Award that will fund ongoing work in the former Levi Garraway research laboratory at Dana-Farber Cancer Institute, Boston, where she works.

But Botta's younger life was somewhat the antithesis of her confined yet wholly distinguished time in the laboratory. “I am from Sorrento, Italy,” she explained proudly, recalling a somewhat idyllic childhood living just steps from the azure Mediterranean Sea in a picture-perfect region. “For 3 months of every year, I would go to the beaches and into the water every day. It was a must; it was our culture. The Mediterranean is really warm, so when I moved here I had to deal with the cold ocean water and this different culture where people go to the beach, magnificently vast, to sit on the sand. In Sorrento, we want to be in the water,” she added with humor.

Botta noted that life in Sorrento maintained a different sort of tempo. While tiny winding streets crowded with Vespas were often congested, life itself was more slow-paced. “If we wanted to go somewhere, we just jumped on a scooter and off we went,” she said, as if channeling a younger Sophia Loren. In her spare time, Botta played tennis at a competitive level.

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Boston Strong

Having met her future husband during a lab internship at University of Naples Federico II in Naples where she received her PhD in molecular oncology, Botta and her then-fiancé decided to send letters of applications for postdoctoral work to various institutions throughout Europe and the U.S.

When Harvard reached out to both of them, they embarked on what would be her very first trip to the U.S. “We had a deal,” said Botta. “If I didn't like the city, we wouldn't move here.” But Boston proved “... fantastic. It is a European-style city, somewhat relaxed. There is a lot of history, culture, beautiful churches, and the city is very walkable and you really don't need a car. Plus, in such a young and professional city, I happened to meet people from my hometown—unbelievable! This city never stops surprising us. Whenever I am flying in, I fall in love with it all over again when I glimpse the beautiful landscape that the Boston Harbor offers.”

Most convincing of all has been the outstanding work being done in laboratories. She and her husband, now a senior scientist at Merck, were both postdoc fellows at Harvard University for a few years, during which time their appreciation of the Boston scientific community grew. “When we saw the level of research people do here, we felt very lucky we were selected to come,” said Botta.

Now the proud mother of 2-year-old daughter, Virginia Elizabeth, Botta remarked, “I'm so glad to raise my daughter in a city that has so much to offer to children, although we put lots of efforts in teaching her the Italian language and culture, as well.” Since completing her stint at Harvard, Botta has served for 5 years as a postdoctoral fellow at Dana-Farber Cancer Institute and was promoted to research scientist following her Young Investigator award, which she called “a great honor and the coronation of my postdoctoral work.”

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Detailing the Work

Botta told Oncology Times, “During the training at Dana-Farber Cancer Institute and the Broad Institute, my work has been focused on the study of molecular basis of prostate cancer, and in particular on the discovery of novel genes playing key roles in the resistance of this disease to existing therapies.”

She explained that the current clinical therapies used in prostate cancer rely on agents able to suppress androgen production (androgen deprivation therapy), since prostate cancer cells depend on the presence of this hormone. “After an initial response to therapy, however, in many cases tumors reappear, progressing to a castration-resistant prostate cancer (CRPC) stage. Resistance to ADT remains the major cause of death for prostate cancer patients,” Botta said. “A comprehensive understanding of resistance to ADT remains an important unmet medical need in advanced prostate cancer. Therefore, the main focus of our research is to identify novel genetic determinants of prostate cancer that confer resistance to clinical therapies and may aid in the development of new therapeutic strategies.”

Botta credits Dana-Farber and the Broad Institute for giving her a unique opportunity to utilize cutting-edge approaches to acquire the skills necessary to discover new genes playing key roles in the resistance of prostate cancer to existing therapies.

“We carry out genome-wide screenings on cancer cell lines—a powerful approach for the identification of resistance mechanisms in the context of drug treatment. With this work, we were able to show that genetic loss of PLZF gene represents a mechanism promoting resistance to ADT and CRPC phenotype,” explained Botta. The work has resulted in publication (Cancer Res 2015;75(10):1944-1948), and another manuscript will be soon submitted for publication.

“We are fortunate to have the opportunity to access and sequence tumor tissue from Dana-Farber Cancer Institute and Brigham and Women's Hospital CRPC patients, together with samples derived from the Stand Up to Cancer-PCF Prostate Dream Team (SU2C-PCF),” detailed Botta. “This approach allows us to combine the relevant findings emerging from the functional screenings with genomic alterations found in CRPC tumor samples.

“This translational research has the real potential not only to highlight novel biological mediators of resistance to therapies, but also to aid the design of novel agents to prevent the emergence of resistance,” she continued. “Thus, such studies might ultimately lead to the development of new, more efficient combinatorial strategies beneficial for patients with such incurable tumors as the castration-resistant prostate cancer.”

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Looking Forward, Yet Glancing Behind

Botta said she feels very fortunate being a member of a lab conducting such creative and stimulating research. “By leveraging sophisticated techniques, we aim to discover novel mediators in the resistance of tumors to the current anticancer treatments. This approach may open new frontiers to precision, or ‘personalized,’ medicine, with the ultimate goal of customizing predictive, diagnostic, or prognostic decisions to each patient. This work inspires young investigators like myself in making a significant contribution to curing cancer, and provides invaluable hopes for patients and families affected by such incurable tumors.”

And yet, with such a complexity of scientific understanding and research goals firmly in mind, there are still times when Sorrento calls to her.

“What do I miss?” she asked rhetorically. “My family. The ability to easily travel across borders and throughout Europe. And every day I miss the food. People here think Italians eat nothing but pasta and pizza. But they are wrong. We eat fresh fish from the Mediterranean and fresh vegetables. But when colleagues came to my house for an Italian cooking lesson, what did I make? Homemade pizza,” she laughed. “And trust me, there is no chicken or pineapples on a true Italian pizza...and no white sauce. When you are Italian, only red sauce will do.”

Valerie Neff Newitt is a contributing writer.

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