MSK Research Highlights, February 12, 2024

New research from Memorial Sloan Kettering Cancer Center (MSK) investigates overcoming drug resistance in chronic lymphocytic leukemia; describes a new method for identifying driver mutations in tumor samples; identifies a protein that orchestrates macrophages’ cancer-fighting abilities; and uncovers how cancer programs could do more to help patients quit smoking.

Overcoming resistance to BTK inhibitors for chronic lymphocytic leukemia

People with chronic lymphocytic leukemia (CLL) can be effectively treated with drugs called Bruton’s tyrosine kinase (BTK) inhibitors, which target the BTK enzyme. However, many patients start to resist these drugs as the cancer cells develop mutations. One form of resistance impedes the drugs from binding to their targets. In 2022, a team led by MSK hematologic oncologist Omar Abdel-Wahab, MD, found that BTK mutations can also cause a “scaffolding activity,” meaning that they organize and regulate the signaling of other enzymes that drive cancer cell growth.

In new research, Dr. Abdel-Wahab, along with co-corresponding authors Gwenn Hansen, PhD, of Nurix Therapeutics, and Justin Taylor, MD, of Sylvester Comprehensive Cancer Center, report that a newly discovered clinical-grade BTK degrader compound called NX-2127 can disrupt the scaffolding function and overcome resistance to BTK inhibitors.

A phase 1 clinical trial, NX-2127, led at MSK by hematologic oncologist and CLL expert Meghan Thompson, MD, showed clinical benefit in CLL patients and could offer a way to treat tumors resistant to current BTK inhibitors. (Several BTK degraders are in active clinical trials for CLL and B cell lymphomas at MSK now.)

Read more in Science, including a related perspective on the drug strategy saying the study “predicts a promising clinical future for degraders.”

A new method for identifying driver mutations in tumor samples

Cancer is a disease caused by the accumulation of genetic mutations, and tests such as MSK-IMPACT^® allow doctors to identify potential cancer-associated mutations present in a tumor sample. But because there are usually many mutations detected, it can be difficult to determine which ones are the “driver” mutations — those actually causing the cancer to grow and spread — and which are “passengers” just going along for the ride. Investigators at MSK have devised a new statistical and computational method for teasing out whether a particular mutation is a driver. They named this method MAGPIE (mutual exclusivity analysis of cancer-associated genes and variants and their probability of being drive).

The creation of MAGPIE was co-led by Colin Begg, PhD, Chair of Epidemiology and Biostatistics at MSK, and colleagues Xinjun Wang, PhD, and Ronglai Shen, PhD. MAGPIE uses the mathematical assumption of mutual exclusivity of driver mutations within oncogenic pathways to compute the probability that a gene is a driver gene and to further identify important variants within those candidate driver genes. It already has been applied to a large study of primary melanomas using MSK-IMPACT^® sequencing. Identifying driver mutations is an important aspect of precision oncology, including matching individual patient with the best treatments for their cancers. Read more in the American Journal of Human Genetics.

MSK researchers identify protein that orchestrates macrophages’ cancer-fighting abilities

The activation of macrophages — white blood cells that play a key role in the immune response — is controlled through a balance of receptors that promote or inhibit their activity. This check and balance helps protect healthy tissues during infection, but it can also allow tumor cells to escape. A new study from the lab of MSK immunologist Frederic Geissmann, MD, PhD, reveals that a protein called ID3 controlled this balance in a type of macrophage found in the liver called Kupffer cells. Moreover, by shifting the balance of inhibition and activation, ID3 gave these macrophages the ability to engulf tumor cells and activate a broader anti-cancer response. The experiments, which were led by Zihou Deng, PhD, a senior research scientist in the Geissmann Lab, found that ID3 could confer anti-tumor properties to other types of macrophages, too, including those derived from mouse bone marrow and human pluripotent stem cells. The findings suggest ID3’s role in orchestrating macrophages’ tumor-fighting abilities could potentially be harnessed as a cancer therapy. Read more in Nature.

Cancer programs could do more to help patients quit smoking

A national survey of 762 Commission on Cancer-accredited cancer programs finds nearly all (90%) report asking patients about smoking behavior and advising cessation to those currently smoking. However, less than half of programs (42%) report regularly assisting patients with smoking cessation, and few programs report providing routine access to evidence-based clinical recommendations such as behavioral counseling (18%) or prescribing medications to quit smoking (18%).

The study was conducted by the Just ASK national quality assessment initiative, undertaken by the American College of Surgeons, and these findings are believed to be the largest ever reported on the quality of smoking cessation efforts in community oncology settings. Principal barriers to promoting smoking cessation include lack of staff training (69%), lack of designated tobacco treatment specialists (62%), and perceived patient resistance (58%). The report urges “greater attention to staff training and practice facilitation to adopt best practices for tobacco treatment throughout diverse cancer care settings.” Jamie Ostroff, PhD, Chief of MSK’s Behavioral Sciences Service and Director of the Tobacco Treatment Program, is the lead author of the paper and notes that “MSK is well recognized as a clinical, research, and training leader in implementing tobacco treatment in cancer care.” Read more in JCO Oncology Practice.