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  • Turning Point 2012

    Silencing the Signals

    Scientists find pathways that control cell growth in endometrial and cervical cancer

    Eileen Duffey-Lind, RN, MSNEileen Duffey-Lind, RN, MSN, a pediatric nurse at Dana-Farber, honors her sister, Maureen. 

    Despite seeing the effects of cancer on a daily basis, Eileen Duffey-Lind, RN, MSN, a pediatric nurse practitioner at Dana-Farber, was unprepared when her sister, Maureen, was diagnosed with cervical cancer in 2003.

    After treatment, Maureen's cancer remained in remission for three years before it came back with a vengeance. The aggressive disease and intolerable side effects of an investigational drug took their toll, and Maureen died in December 2006, at age 37.

    "Because I deal with cancer on a regular basis, I thought I could handle anything that came my way when my sister was diagnosed," writes Duffey-Lind on the website for Team Maureen, the fundraising and support vehicle she established as a promise to keep Maureen's spirit alive.

    "Yet I soon realized that nothing could be further from the truth. Because of her cancer diagnosis, I was given the opportunity to see things through the patient's eyes, not just the provider's."

    Money raised by Team Maureen, through the Pan-Massachusetts Challenge bike-a-thon and other activities, supports research on cervical cancer at Dana-Farber. Research directed by Ursula Matulonis, MD, medical director of Gynecologic Oncology Program at the Susan F. Smith Center for Women's Cancers at Dana-Farber and Maureen's doctor, is aimed at better understanding the molecular mutations that drive cervical cancer, and identifying new therapeutic approaches for patients with few treatment options once the cancer has recurred.

    Although cervical and endometrial cancers often don't receive the attention that breast cancer does, Dr. Matulonis considers them "extremely important cancers" that affect thousands of women worldwide.

    Endometrial cancer, which forms in the lining of the uterus, is the most prevalent gynecologic malignancy in the U.S. (twice as common as ovarian cancer). Cervical cancer, a slow-forming malignancy, is the second most common women's cancer killer in the world after breast cancer, especially among women in developing countries.

    Early detection, either through screening with Pap tests (in the case of cervical cancer) or paying attention to warning signs such as abnormal vaginal bleeding or spotting (for endometrial cancer), means that many of these cancers are found at an early stage when treatment is more effective.

    There is increasing emphasis at Dana-Farber, however, on research and treatment of endometrial and cervical cancers, particularly at advanced stages, says Dr. Matulonis.

    Andrea Myers, MD, PhD, a medical oncologist at Dana-Farber, directs clinical trials of drugs that target mutations driving the development of endometrial cancer. One, a multicenter phase II trial funded through a Stand Up To Cancer grant, is examining genetic mutations that result in the activation of the PI3K signaling pathway, which promotes the uncontrolled cell growth powering tumor development.

    Endometrial cancer has one of the highest rates of genetic mutations in the PI3K pathway. A common mechanism of PI3K activation occurs when a tumor suppressor called PTEN (phosphatase and tensin homolog) and a PI3K subunit, which is encoded by the cancer-causing PI3KCA gene, are silenced.

    In addition, studies have shown that the activity of the PI3KCA gene is cranked up like the volume of a teenager's iPod in the most aggressive forms of endometrial cancer. PI3K also interacts with another important cancer-growth pathway, called RAS-ERK. Many experts feel that this interaction may foster drug resistance and render treatment unsuccessful.

    The Myers trial enrolls women with advanced, recurrent, or persistent endometrial cancer and treats them with MK-2206, an investigational drug that affects an important component of the PI3K signaling pathway called "akt" that promotes cell survival.

    Tissue samples are collected from patients and examined via high-throughput genetic analysis during the course of treatment to determine the presence or absence of mutations that lead to PI3K activation. The researchers will use this genetic information to assess patients' response to MK-2206.

    "We hope to use information about the genetics of patients' tumors to assess their response to certain targeted drugs," says Dr. Myers. "As such, treatments can be optimized to each patient in the safest and most effective way possible."

    While the standard treatments for cervical cancer – surgery, pelvic radiation, and chemotherapy – can be effective, very few new options have been developed in nearly a decade.

    Mark ByrneA gene-scanning tool known as OncoMap has made it possible to study the genetic mutations behind endometrial and cervical cancer. Mark Byrne, a technologist at Brigham and Women's Hospital, prepares samples of tumor tissue for analysis. 

    Dana-Farber physician-scientist Alexi Wright, MD, studies the genetic mutations of cervical cancer. She is currently taking tissue samples from 70 patients at all stages of disease, including adenocarcinomas (a more aggressive form of the disease, which can be missed on Pap smears) and squamous cell carcinomas (which account for the vast majority of cases), to determine if there are common or different mutations across these subtypes.

    Her team used a mass spectrometry tool called OncoMap, developed at Dana-Farber, to analyze the genetic makeup of cancer cells and ferret out mutations in tumor DNA for which targeted therapies already exist or are in development.

    So far, Dr. Wright and her colleagues discovered that 34 percent of the cancers they analyzed had mutations in the PI3K pathway, the same signaling pathway being studied by Dr. Myers. They also found distinct mutations in squamous cell carcinomas and adenocarcinomas, suggesting different therapeutic rationales for each subtype.

    This is one of the largest groups of cervical cancer tumor samples studied to date, and the findings suggest that targeted therapies tailored to the tumor type, rather than more generalized approaches, may be more effective than existing therapies.

    PI3K inhibitors are currently in clinical trials, mostly for endometrial cancer, but are now beginning in cervical cancer, as well. Dr. Wright presents her research at the 2012 meeting of the American Society of Clinical Oncology.

    "This research inspires me," says Dr. Wright, "because a lot of people seem to think that cervical cancer has been taken care of in the U.S. due to Pap smears that provide early detection and the human papillomavirus vaccine that offers prevention. It's almost as if it's become a forgotten disease. But each patient diagnosed with cervical cancer desperately needs options."

    A better molecular understanding of cancer has yielded new discoveries, summarizes Dr. Matulonis, but to date there has been little research investigating the genetic drivers in gynecologic cancers. Dana-Farber has made a concerted effort to get patients into selected phase I clinical trials of new targeted therapies, and several trials have gone on to phase II because of patients' responses.

    "The incidence of endometrial cancer is rising in the U.S.," she says. "And cervical cancer is a major health problem worldwide, especially in developing countries. It is our mission at Dana-Farber to make a difference."

    Turning Point 2012 

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