AACR meeting highlights new findings on drug resistance, targeted therapies

Authors

  • Carrie Printz


Following are highlights from a few of the studies presented at the American Association of Cancer Research annual meeting, held April 6 through 10, 2013, in Washington, DC.

RNA Interference Safe

A phase 1 study evaluating the safety of RNA interference (RNAi) was among the research presented at the meeting. Safety and preliminary efficacy results from that study indicated that TKM-080301 (also known as TKM-PLK1) can be safely administered in humans, according to Ramesh Ramanathan, MD, medical director of the Virginia G. Piper Cancer Center Clinical Trials Program at Scottsdale Healthcare and deputy director of the Translational Genomics Research Institute in Phoenix, Arizona.

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RNAi can potentially “turn off” genes’ coding for proteins that contribute to cell division, said Dr. Ramanathan. TKMPLK1 specifically targets a gene called polo-like kinase 1 (PLK1), which codes for a protein involved in tumor cell growth. Researchers previously have found that PLK1 is present in many types of cancer, including aggressive disease. Dr. Ramanathan and colleagues’ preclinical results demonstrated that decreasing PLK1 levels in cancer cells can stop tumor growth and kill the cells.

Vemurafenib-Resistant Tumors Exhibit Slower Growth After Treatment End

Another study presented at the meeting indicated that vemurafenib-resistant tumors in patients with melanoma exhibited slower growth after the treatment was ended, and that drug resistance was overcome by intermittent treatment in animal models.

Although investigators were initially excited to find that vemurafenib effectively treated BRAF mutations in patients with melanoma, they also were disappointed when patients stopped responding to the therapy after 6 to 8 months, said Darrin Stuart, PhD, senior research investigator at the Novartis Institutes for BioMedical Research in Emeryville, California. BRAF mutations are found in more than one-half of patients with melanoma, but most develop recurrence with drugresistant disease, he added.

In a previous mouse study, Dr. Stuart and his colleagues learned that tumors that developed vemurafenib resistance eventually became dependent on the drug to grow; when the treatment was stopped, the tumors stopped growing. To determine whether this process also occurred in humans, investigators evaluated tumor scans of 19 patients with vemurafenib-resistant tumors. Of those, 14 showed a decrease in their rate of tumor growth when the drugs were stopped. The researchers also implanted mice with human tumors and treated them with vemurafenib either continuously or intermittently. Those receiving the intermittent dose did not develop drug resistance.

KDM1: A Potential Treatment for Glioma

Researchers from the University of Texas Health Science Center in San Antonio presented preclinical findings that the protein KDM1 is a potential therapy for patients with glioma. Gangadhara Sareddy, PhD, and his colleagues found that KDM1 expression is upregulated in gliomas and that inhibiting it could improve treatment for the disease. The majority of patients with malignant gliomas have a survival period of approximately 14 months. Glioma development is a multistep process that involves both genetic and epigenetic changes. The latter is reversible and, therefore, targeting epigenetic mechanisms is a promising avenue for therapy, Dr. Sareddy added.

Investigators silenced KDM1 expression with siRNA or inhibited it with pargyline or NCL-1 and found that reducing its expression or inhibiting it pharmacologically reduced glioma cell line growth in vitro. It also reduced the growth of patientderived primary glioblastoma multiforme cells in vitro and human glioma cell lines in mice. Researchers also found that inhibiting KDM1 increased the expression of tumor suppressor p53 genes through epigenetic modifications.

Black Women with Breast Cancer Have Poorest Survival Rates

In another study presented at the meeting, black women with breast cancer were shown to have significantly worse survival than women of other racial and ethnic groups regardless of cancer subtype. The results suggest that survival differences are not just because black women are more frequently diagnosed with less-treatable subtypes.

Candyce Kroenke, MPH, ScD, a research scientist at Kaiser Permanente Division of Research in Oakland, California, and her colleagues assessed the link between race and breast cancer survival in a prospective cohort of 1688 breast cancer survivors enrolled in the Life After Cancer Epidemiology and Pathways studies who were being treated for luminal A, luminal B, basal-like, or HER2-enhanced breast cancer. They found that, consistent with previous studies, black women were nearly twice as likely to die of breast cancer compared with white women. Black women also were more likely to have the hard-to-treat, triple-negative breast cancer subtype and a lower likelihood of the more treatable luminal A subtype.

Nevertheless, poor prognosis among black women was consistent across all tumor subtypes, researchers found. Compared with white women, black women were 2.3 times more likely to die of luminal A disease, 2.6 times more likely to die of luminal B disease, 1.3 times more likely to die of the basal-like subtype, and 2.4 times more likely to die of the HER2-positive subtype of breast cancer.

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