C. Kent Osborne, M.D., director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine and president of the symposium, hosted a Drugs in the Pipeline press conference on Friday, Dec. 11, at 8:00 a.m. CT, in room 217C of the Henry B. Gonzales Convention Center. (A recording is available below.)
The following abstracts were presented at the press conference:
48. Targeting Intrinsically-Resistant Breast Cancer Stem Cells with Gamma-Secretase Inhibitors
Treating breast cancer with a “Notch” pathway inhibitor reduced the ability of cancer stem cells to replenish themselves and promote tumor growth, researchers reported at the CTRC-AACR San Antonio Breast Cancer Symposium. These findings suggest that ongoing clinical trials testing this class of agents could offer promising results, especially when combined with other anticancer treatments.
“The Notch pathway regulates self-renewal of stem cells and our research indicates that it also regulates cancer stem cell self-renewal,” said the study’s lead author, Jenny Chang, M.D., professor of medicine at Baylor College of Medicine.
The impact of using a Notch inhibitor, she said, was to sensitize a significant proportion of otherwise treatment-resistant cancer stem cells, and this supports the notion that a select subpopulation of cells in breast cancer is largely responsible for disease recurrence and cancer spread.
Researchers from Baylor College of Medicine, University of Michigan and Dana-Farber Cancer Institute focused on “mammosphere-forming” human breast cancer cells – cells that have been found to have stem cell properties and are resistant to conventional chemotherapy. These cancer cells can be identified because of their protein signature; they express high levels of CD44, a protein involved in migration, and low or undetectable levels of the cell adhesion protein CD24. Gene analysis of these cells showed that a number of pathways are activated, such as Notch, PI3K and Hedgehog, compared to non-cancerous cells.
In this study, researchers tested gamma-secretase inhibitors in preclinical cancer stem cell models and a complementary clinical trial of a gamma-secretase inhibitor in breast cancer patients. Gamma-secretase is required for activation of the Notch signaling pathway, which regulates self-renewal of stem cells.
The research team implanted human triple-negative breast cancer obtained from patients in two independent sets of mice, and then treated them with a gamma-secretase inhibitor. They isolated the tumors in the mice and found that mammosphere formation was impaired, but tumor volume was not affected.
“Because the cancer stem cell population may be a very small percentage of the tumor cells (0.1 percent to 1 percent), tumor volume measurement is not sensitive enough to measure effects on the cancer stem cell population,” Chang said.
Researchers then studied tumor biopsies taken from a patient with metastatic breast cancer enrolled in a complementary clinical trial of a gamma-secretase inhibitor conducted at Baylor College of Medicine. They looked at biopsies before and during treatment. Findings showed that mammosphere-forming efficiency declined after the first cycle of the agent combined with chemotherapy, and tumor response was seen only after several rounds of therapy.
“The agent reduced the tumorigenic cancer cells,” Chang said. “To eliminate these cells, combination therapy that targets additional pathways regulating cancer stem cells will be essential.”
25. CONFIRM: A Phase III, Randomized, Parallel-Group Trial Comparing Fulvestrant 250 mg vs Fulvestrant 500 mg in Postmenopausal Women with Estrogen Receptor-Positive Advanced Breast Cancer
Embargoed until 4:00 p.m. CT, Dec. 10, 2009
A higher dose of fulvestrant is well tolerated and more active than the standard, lower dose in postmenopausal patients with advanced breast cancer.
“We believe that, based on the results of this study, treatment and practice should change; patients should receive the 500 mg dose,” said Angelo Di Leo, M.D., Ph.D., director of the Department of Oncology at the Hospital of Prato, Italy.
Fulvestrant, sold under the trade name Faslodex by AstraZeneca, is an estrogen receptor antagonist used for the treatment of metastatic receptor-positive breast cancer in women who have progressed or had recurrent cancer after prior endocrine therapy.
Di Leo and colleagues conducted the CONFIRM study – Comparison of Faslodex In Recurrent or Metastatic breast cancer – to compare the efficacy, response rate, clinical benefit, duration of benefit and response, quality of life and overall survival of the drug at the standard 250 mg per month dose and 500 mg per month dose. Over a two-year period, the researchers recruited 736 women from 128 centers located in 17 countries to participate in this study.
Findings showed that the 500 mg dose of fulvestrant was more active and as well tolerated as the 250 mg dose of fulvestrant, according to Di Leo, who will present further results of this randomized, phase III trial at the CTRC-AACR Annual San Antonio Breast Cancer Symposium, to be held Dec. 9-13, 2009.
The researchers are currently conducting the Trans-CONFIRM study in an effort to understand if the higher dose is mandatory in all patients, or only some.
44. A Double-Blind, Randomized, Placebo-Controlled, Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib in Combination with Paclitaxel as a First-Line Therapy in Patients with Locally Recurrent or Metastatic Breast Cancer
Combining chemotherapy with a drug widely used to treat liver and kidney cancer has offered advanced breast cancer patients with HER2-negative tumors significant improvement in overall response rate and time-to-disease progression, according to new results from an international trial presented at the CTRC-AACR San Antonio Breast Cancer Symposium.
The combination of sorafenib and paclitaxel also demonstrated a favorable trend in progression-free survival, according to lead investigator William Gradishar, M.D., professor of medicine at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University. Data on overall survival are not yet available.
“These data indicate that sorafenib provides added benefit when combined with paclitaxel compared to single agent paclitaxel in the first-line treatment of advanced breast cancer,” Gradishar said.
The study, a double-blind, randomized, placebo-controlled phase IIb study, was conducted in the United States (95 patients), India (170 patients) and Brazil (15 patients). It is the second in a series of four worldwide stage IIb clinical trials testing the use of sorafenib in recurrent or metastatic HER2-negative breast cancer in a program called TIES (Trials to Investigate the Effects of Sorafenib in breast cancer).
The first study to be reported demonstrated a significant progression-free survival benefit in patients with advanced breast cancer who were treated with capecitabine chemotherapy and sorafenib, compared to treatment with capecitabine alone. The other two studies are ongoing.
Sorafenib is an oral agent that has been shown to target members of two classes of kinases involved in cell growth and angiogenesis, the growth of blood vessels to feed tumors. It is approved to treat advanced kidney cancer and liver cancer. Paclitaxel is used to treat a number of different cancers, including both early and advanced breast cancer.
Early research suggested sorafenib may be a promising treatment for breast cancer, and initial clinical studies demonstrated it has a modest activity as a single agent in patients with metastatic disease.
To see if benefit improved when sorafenib was paired with chemotherapy, the researchers randomized 119 patients to the combination therapy and 118 patients to a placebo and paclitaxel.
Results showed median progression-free survival was 6.9 months (combination therapy) vs. 5.6 months (placebo/paclitaxel). Median time-to-progression was 8.1 months vs. 5.6 months for patients receiving sorafenib/paclitaxel compared to placebo/paclitaxel. The overall response rate was 67 percent vs. 54 percent, respectively.
Discontinuation of study treatment due to adverse events occurred in 23 patients in the combination arm compared to five patients in the placebo/paclitaxel arm. With the exception of neuropathy, more grade 3 and 4 toxicities occurred in patients who received sorafenib/paclitaxel. Treatment-related deaths occurred in two patients in the combination treatment arm.
“There were no new toxicities observed with the combination and adverse events were manageable,” Gradishar said.
67. Targeting Aldose Reductase: A Novel Strategy in Treating Endocrine Resistance Using Combination Therapy
Treating estrogen receptor-positive breast cancer tumors with a combination of fidarestat (an inhibitor of aldose reductase enzyme) and letrozole (an aromatase inhibitor) could delay or stop tumor resistance to endocrine therapy, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium.
“Single agents are less effective,” said Rajeshwar Rao Tekmal, Ph.D., professor of obstetrics and gynecology at the University of Texas Health Science Center at San Antonio. “Many tumors develop resistance, so this combination approach could prolong that window when endocrine therapy is effective.”
About two-thirds of breast cancer tumors initially are hormone sensitive or estrogen receptor-positive and respond well to endocrine therapy. However, close to half of those tumors develop resistance to endocrine therapy, said Tekmal.
In this preclinical study, researchers treated estrogen receptor-positive tumors already resistant to letrozole with letrozole and fidarestat. As an inhibitor of aldose reductase enzyme, fidarestat blocks the metabolism of glucose in cancer cells.
Together, the combination effectively re-sensitized the cells to letrozole, allowing for effective endocrine therapy and more cell death.
Researchers believe increased glucose metabolism (polyol accumulation) contributes to oxidative stress, which, in turn, could alter intracellular signalling by affecting the regulation of protein kinases that are known to be involved in therapy resistance. Blocking the path of glucose metabolism may help to restore sensitivity to endocrine therapies or it may stop or delay the development resistance endocrine therapies in first place.
While this is a preclinical study, Tekmal believes it could lead to future drug treatments that will make endocrine therapy more effective for longer periods of time.
“This is a very promising study showing that combination treatments seem to work on resistance and re-sensitizing tumors that are resistant to endocrine therapies,” he said.
Download* the mp3 of the teleconference (13.2 MB, 58 minutes and 04 seconds)
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The mission of the CTRC-AACR San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for breast cancer patients. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR) and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor, and the AACR’s scientific prestige in basic, translational and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. The 32nd annual symposium is expected to draw more than 8,500 participants from more than 90 countries.
In San Antonio, Dec. 9-13: