The gist: Drugs called gamma secretase inhibitors (GSI) are being explored as a potential way to overcome resistance to endocrine therapy drugs (like tamoxifen or letrozole) for women with estrogen-receptor-positive (ER+) breast cancer. A GSI drug called MK-0752 was recently given to patients in a clinical trial. The researchers found 18 tumor genes that could be used to predict how well GSI might work for a given patient. A larger study will explore the gene “signature” and measure just how effective GSI drugs are for breast cancer patients.
“Loyola researchers and collaborators have reported promising results from a novel therapeutic approach for women with estrogen-receptor-positive breast cancer.
“The new approach, a new drug class called gamma secretase inhibitors (GSI), specifically inhibits Notch and shuts down critical genes and cancer cells responsible for tumor growth.
“Kathy Albain, MD, FACP, who led the study, will present findings Dec. 11 during the 2014 San Antonio Breast Cancer Symposium.
“Existing cancer drugs are effective in killing mature breast cancer cells. But a handful of immature breast cancer stem cells are resistant to such drugs. They survive and are responsible for tumor growth and progression. Resistance to standard therapy is a major cause of death in women with estrogen-receptor-positive breast cancer. Approximately 75 percent of breast cancers are estrogen-receptor positive…
“Researchers are planning a larger, phase II study to evaluate the efficacy of the GSI class of drugs added to endocrine therapy versus endocrine therapy alone. This study also will determine how well the 18 gene “signature” will predict who responds to therapy.
” ‘This is an exciting new strategy to overcome resistance to a very common class of drugs (tamoxifen, letrozole), so it is our hope that in the future a vast number of patients with estrogen-receptor-positive breast cancer could benefit,’ Dr. Albain said.”
While medical research has produced significant treatment innovations for many cancer types, so far little has changed for small cell lung cancer (SCLC). Current treatment guidelines recommend chemotherapy with etoposide (Etopophos) and cisplatin (Platinol), drugs than are more than 30 years old. Relapse is common, and survival rates remain low. Now, the new PINNACLE clinical trial will investigate a new drug against SCLC. Patients with extensive-stage SCLC who have never received any other cancer treatment will be treated with Etopophos and Platinol either by themselves or in combination with the new drug, OMP-59R5. The drug acts by inhibiting NOTCH, a protein involved in cell development and growth that plays a role in various cancers. For more information, call 646-888-4203.
Zheng Y, de la Cruz CC, Sayles LC, Alleyne-Chin C, et al. Cancer Cell. Jul 8, 2013.
Sustained tumor progression has been attributed to a distinct population of tumor-propagating cells (TPCs). To identify TPCs relevant to lung cancer pathogenesis, we investigated functional heterogeneity in tumor cells isolated from Kras-driven mouse models of non-small-cell lung cancer (NSCLC). CD24+ITGB4+Notchhi cells are capable of propagating tumor growth in both a clonogenic and an orthotopic serial transplantation assay. While all four Notch receptors mark TPCs, Notch3 plays a nonredundant role in tumor cell propagation in two mouse models and in human NSCLC. The TPC population is enriched after chemotherapy, and the gene signature of mouse TPCs correlates with poor prognosis in human NSCLC. The role of Notch3 in tumor propagation may provide a therapeutic target for NSCLC.
Hassan KA, Wang L ... Kalemkerian GP, Wicha MS, Clin Cancer Res, Feb 26, 2013
The cancerstem cell theory postulates that tumors contain a subset of cells with stem cell properties of self-renewal, differentiation and tumor-initiation. The purpose of this study is to determine the role of Notchactivity in identifying lungcancerstemcells.
Notchactivity can identify lungcancerstemcell-like population and its inhibition may be an appropriate target for treating lungadenocarcinoma.