FDA approved leukemia drugs shows promise in ovarian cancer cells

The drug Sprycel, approved for use by the U.S. Food and Drug Administration in patients with chronic myeloid leukemia, significantly inhibited the growth and invasiveness of ovarian cancer cells and also promoted their death, a study by researchers with UCLA's Jonsson Comprehensive Cancer Center found.

The drug, when paired with a chemotherapy regimen, was even more effective in fighting ovarian cancer in cell lines in which signaling of the Src family kinases, associated with the deadly disease, is activated.

The study appears in the Nov. 10, 2009 edition of the British Medical Journal.

Ovarian cancer, which will strike 21,600 women this year and kill 15,500, causes more deaths than any other cancer of the female reproductive system. Few effective therapies for ovarian cancer exist, so it would be advantageous for patients if a new drug could be found that fights the cancer, said Gottfried Konecny, an assistant professor of hematology/oncology, a Jonsson Cancer Center researcher and first author of the study.

"I think Sprycel could be a potential additional drug for treating patients with Src dependent ovarian cancer," Konecny said. "It is important to remember that this work is only on cancer cell lines, but it is significant enough that it should be used to justify clinical trials to confirm that women with this type of ovarian cancer could benefit."

Recent gene expression studies have shown that about one-third of women have ovarian cancers with activated Src pathways, so the drug could potentially help 7,000 ovarian cancer patients every year.

In this study, the UCLA team tested the drug against 34 ovarian cancer cell lines and they conducted genetic analysis on all cell lines. Through these analyses, the researchers were able to identify genes that predict response to Sprycel. If the work is confirmed in human studies, it may be possible to test patients for Src activation and select those who would respond prior to treatment, personalizing their care.

"We were able to identify markers in the pre-clinical setting that would allow us to predict response to Sprycel," Konecny said. "These may help us in future clinical trials in selecting patients for studies of the drug."

Sprycel is what is known as a "dirty" kinase inhibitor, meaning it inhibits more than one pathway. Konecny said it also inhibits the focal adhesion kinase and ephrin receptor, also associated with ovarian cancer.

The next step, Konecny said, would be to test the drug on women with ovarian cancer in a clinical trial. The tissue of responders would then be analyzed to determine if the Src and other pathways were activated. If that is confirmed, it would further prove that Sprycel could be used to fight ovarian cancer. In studies, women would be screened before entering a trial and only those with Src dependent cancers could be enrolled to provide further evidence, Konecny said, much like the studies of the molecularly targeted breast cancer drug Herceptin enrolled only women who had HER-2 positive disease.

"Herceptin is different because we knew in advance that the only worked in women with HER-2 amplification," he said. "In this case, we don't clearly know that yet. The data reassure us that the drug works where the targets are over-expressed but we need more testing to confirm this."
The tests combining the drug with chemotherapy are significant because chemotherapy currently is the first line treatment for ovarian cancer patients following surgery. Because Sprycel proved to have a synergistic effect when combined with chemotherapy both made the other work better it may be possible to add the targeted therapy as a first line treatment if its efficacy is confirmed in future studies, adding a new tool to an oncologist's arsenal.

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New Insights, Inroads Against Breast, Ovarian Cancers

"It's nice to be here. It's nice to be anywhere," singer and actress Olivia Newton-John, a self-described 17-year breast cancer "thriver," told reporters at one of the world's largest gatherings of cancer specialists on Sunday.

Newton-John, 60, spoke at a special news briefing on advances and insights in breast and gynecologic cancers, part of the American Society of Clinical Oncology (ASCO) annual meeting in Orlando, Fla.

"I'm very excited about what is going on in the world of cancer treatment," she said. "I feel so fortunate that I can spread the message to other women by saying 'Here I am, 17 years later.'"

But as with every such gathering, researchers delivered both good news and bad news in the war against cancer.

On the bad news front, one study presented at the briefing found that use of the CA125 biomarker to track ovarian cancer did not help guide treatment decisions for women.

Ovarian cancer remains one of the most deadly malignancies primarily because it is typically spotted too late for treatment to be effective. Recently, however, some doctors have turned to blood levels of a molecule called CA125 to screen for the presence of disease, with repeat screens after treatment to gauge the likelihood of a recurrence.

But the new study found that even when CA125 indicated the possibility of cancer relapse and spread, starting additional treatment early did not enhance a woman's survival versus waiting longer for second-line treatment.

For this study, 265 women whose ovarian cancer was in remission after one round of chemotherapy began a second round of chemo as soon as their CA125 levels started to rise. Another 264 women waited until actual signs of a relapse appeared until they began second-line therapy.

This meant that, "patients who were in the early treatment arm started their second-line chemotherapy (based on rising CA125 levels) 4.8 months earlier than those who had waited till signs and symptoms," study author Dr. Gordon Rustin, a professor of oncology at Mount Vernon Cancer Center in Hertfordshire, U.K. , told reporters.

But average overall survival was the same, whether treatment had been guided by CA125 levels or not: 41 months from the completion of the first course of therapy.

"Even more interestingly, the time to third-line therapy was 4.6 months earlier in the earlier-on group," he added. "This indicated that the early initiation of chemotherapy did not induce a longer remission and, despite all this early treatment, did not improve survival."

On the plus side, the findings suggest that rising CA125 levels may not be as dire a marker as once thought, according to the researchers. "For the first time, women can be reassured that there's no benefit from early detection from routine CA125 and they can be told that even if CA125 rises, chemotherapy can be safely delayed until they have signs or symptoms of recurrence," Rustin said. "For the first time ever, women now have informed choices to be able to decide [on testing]. Most of my patients, when given this information, do not want routine CA125 measurements."

The study strikes yet another blow to the notion that CA125 might be the reliable ovarian cancer test everyone is looking for. For example, research published in the April issue of Obstetrics & Gynecology found that combining the CA125 test with transvaginal ultrasound did not help detect ovarian cancer.

The new results may only reinforce that skepticism. "We've put that one [CA125 screening] in the grave so many times it has a zombie-like existence," said Dr. Kelly Marcom, a breast oncologist with Duke Comprehensive Cancer Center and director of the Duke Hereditary Cancer Clinic in Durham, N.C. Still, "I doubt every treating oncologist will stop using this to follow treatment."

Another oncologist agreed. "This study suggests that early detection of metastatic cancer did not improve survival," said Dr. Claudine Isaacs, a medical oncologist with Georgetown's Lombardi Comprehensive Cancer Center in Washington, D.C. Unfortunately, the usefulness of CA125 in initial cervical cancer screening remains "questionable."

But there was good news at the meeting for women battling tough-to-treat breast cancers.

Two new studies found promising results with an entirely new class of drugs, called PARP inhibitors -- the first targeted therapy for so-called "triple-negative" breast cancer. Currently, the 15 percent of breast cancer patients who have this type of aggressive tumor have only the option of surgery and chemotherapy.

Breast cancers associated with the BRCA1 and BRCA 2 gene mutations (which heighten risk) are almost always triple negative, explained Dr. Joyce O'Shaughnessy, lead author of one of the studies and co-director of the Breast Cancer Research Program at Baylor-Charles A. Sammons Cancer Center in Dallas.

About 30 percent of women with triple negative cancer experience a recurrence and, once that happens, only survive a year or so.

In this phase II trial, half of the 120 women with this form of metastatic breast cancer were randomized to receive chemo alone, the other half to chemo plus the PARP inhibitor BSI-201.

Those receiving the combination therapy saw almost a doubling of their survival -- from 5.7 months with chemo alone to 9.2 months when BSI-201 was added in, as well as about a 60 percent reduction in the risk of dying from the disease. There were also no additional side effects as compared with standard chemo.

The second phase II PARP inhibitor trial involved 54 women with advance breast cancer who carried the BRCA1/2 mutations. In this trial, the inhibitors -- especially at the higher of two doses -- succeeded in targeting the weakness in the genes' DNA repair mechanism without affecting healthy cells. Forty-one percent of patients saw their tumors completely disappear, said a British team from Kings College, London. There was a slightly lower response rate in the lower-dose group. Mild nausea and fatigue were the most common side effects.

"The drugs are given orally and it still remains a question as to whether the drugs' benefits will extend beyond this narrow patient population," noted Dr. Eric Weiner, head of ASCO's communication committee and chief of women's cancers at the Dana Farber Cancer Institute in Boston.

"These two studies are very exciting," Marcom said. "It speaks to a really clever understanding of the biology of the cancer."

Two other studies presented at ASCO could represent advances in the treatment of cervical cancer. In one study, led by Dr. Alfonso Duenas-Gonzalez of Mexico's National Cancer Institute, researchers found that adding the chemotherapy drug gemcitabine (Gemzar) to standard chemo and radiation therapy improved both progression-free and overall survival -- but not without notable side effects.

And for women diagnosed with early-stage cervical cancer, the more specific and less invasive prognostic indicator called sentinel-nose biopsy appears just as effective as removal of lymph nodes in the pelvis, according to French researchers at George Pompidou European Hospital, Paris. According to the researchers, opting for biopsy rather than lymph node removal should make tracking the disease much less onerous for patients.

Source : www.forbes.com

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