Focus on Understanding Cancers

HMS affiliates are advancing our understanding of cancer to improve human health

Mutable Lung Tumors Shed Light on Resistance

A detailed analysis of lung tumors that became resistant to targeted drugs has revealed two previously unreported resistance mechanisms. In the March 23 Science Translational Medicine, investigators from Massachusetts General Hospital Cancer Center and HMS also describe how the cellular nature of some tumors actually changes in response to treatment and find that resistance-conferring mutations can disappear after treatment is discontinued. The findings support the importance of monitoring the molecular status of tumors throughout treatment.

“It is really remarkable how much we oncologists assume about a tumor based on a single biopsy,” said lead author Lecia Sequist, HMS assistant professor of medicine at Mass General.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death, and in about 12 percent of patients the tumor is driven by a mutation in the epidermal growth factor receptor (EGFR). Targeted drugs called tyrosine kinase inhibitors (TKIs) block EGFR activity and can halt the growth of such tumors, but resistance usually develops.

To better understand why, the research team analyzed the genotype and the phenotype of tumor samples from 37 NSCLC patients, taken both before TKI treatment and when resistance first appeared. The results validated previously reported mechanisms of resistance and identified two more genetic changes: mutations in another oncogene called PIK3CA and overproduction of the EGFR molecule itself.

Telomerase Inhibitor PinX1 Seen to Suppress Tumors

Multiple independent lung tumors metastasized from breast cancer PinX1 mutant mice. That’s a rare development in single-gene knockout mouse tumor models, says Roderick Bronson, an HMS lecturer on pathology who collaborated with researchers at Beth Israel Deaconess Medical Center. Photo courtesy of Beth Israel Deaconess Medical Center

It’s been nearly 10 years since Beth Israel Deaconess Medical Center scientists Kun Ping Lu and Xiao Zhen Zhou discovered PinX1, the first potent endogenous protein shown to inhibit telomerase in mammals.

Now the scientific team has discovered a critical new function for this telomerase inhibitor.

The investigators reported March 23 in the Journal of Clinical Investigation that low levels of PinX1 contribute to cancer development, providing the first genetic evidence linking telomerase activation to chromosome instability and cancer initiation, and suggesting a new avenue of treatment for cancers.

“Although telomerase is activated in 85 to 90 percent of human cancers, little has been known about the significance of telomerase activation in chromosome instability and cancer initiation,” explains Lu, the paper’s senior author and HMS professor of medicine at BIDMC. “We have discovered, for the first time, a novel role for abnormal telomerase activation in cancer initiation. This suggests that telomerase inhibition using PinX1 or other small molecules may be used to treat certain cancers with activated telomerase.”

Notably, the discovery that most PinX1-mutant mouse tumors share tissues of origin with human cancer types linked to alterations in chromosome 8p23 suggests a possible role for deregulation of the PinX1-telomerase complex in treating several common carcinomas, including breast, lung, liver and gastrointestinal cancers.

Multiple Myeloma Genome Yields Unexpected insights

Scientists have unveiled the most comprehensive picture to date of the full genetic blueprint of multiple myeloma, a form of blood cancer. A study of the genomes from 38 cancer samples has yielded new and unexpected insights into the events that lead to this form of cancer and could influence the direction of multiple myeloma research. This work, led by scientists at the Broad Institute of MIT and Harvard and Dana-Farber Cancer Institute, appeared March 24 in Nature.

Multiple myeloma is the second most common blood cancer in the United States, with about 20,000 new cases diagnosed in this country each year.

The emerging genome-wide picture of multiple myeloma reveals genes never before associated with cancer as well as multiple mutations that disrupt just a handful of common pathways, or chains of chemical reactions that trigger a change in a cell. Individually, each mutation is fairly uncommon and might have remained undiscovered had researchers not looked at such a large collection of samples.

“Already, we can see that mutations are funneling into a limited number of pathways,” said co-senior author Todd Golub, director of the Broad’s Cancer Program and Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber Cancer Institute. “This is a demonstration of the value of looking at more than just a single tumor at great depth.”

From the news offices of Mass General, Beth Israel Deaconess and Dana-Farber