New research from Memorial Sloan Kettering Cancer Center (MSK) uncovers why some leukemia patients stop responding to promising new drugs; examines how bone’s hardness shapes the immune battle against metastasis; shows how a telehealth tobacco treatment program helps cancer patients quit smoking; creates the first atomic-level images of a key phosphate transporter that could inform treatment of ovarian cancer and kidney disease; finds Medicare Advantage patients with cancer receive optimal treatment at lower cost; and studies how much tissue surgeons should remove for tumor–related epilepsy.
Why some leukemia patients stop responding to promising new drugs
For years, doctors have treated chronic lymphocytic leukemia (CLL) with drugs called BTK inhibitors, which block a protein that helps cancer cells survive and multiply. Unfortunately, many patients eventually develop resistance, and the drugs stop working.
Newer drugs called BTK degraders were designed to overcome this problem by destroying, rather than blocking, the BTK protein. Early clinical trials have shown promising results, with response rates exceeding 80% in patients who have failed other treatments. But with these drugs, too, patients may eventually develop resistance.
In a recent study led by MSK scientists, researchers analyzed samples from CLL patients treated with the BTK degraders zelebrudomide or bexobrutideg. The team, including leukemia specialist Meghan Thompson, MD, discovered that when these newer drugs stopped working, a genetic mutation called BTK A428D was present in some of the patients’ tumors. Importantly, the team found this mutation existed at low levels before treatment even began, and that by killing off normal cancer cells, BTK degraders inadvertently gave the BTK A428D cells room to grow and take over.
After learning the mechanism by which this takeover occurs, further research suggested a possible way around it: An existing leukemia drug called venetoclax could be combined with BTK degraders to eliminate cells both with and without the BTC A428D mutation. Laboratory experiments in cancer cells confirmed this combination worked.
“Our discovery about a key resistance mechanism in CLL cells has suggested a new approach that may eventually benefit patients,” says physician-scientist and co-first author Quinlan Sievers, MD, PhD, a member of MSK’s Lymphoma Service and the Omar Abdel-Wahab Llab in the Sloan Kettering Institute. “Based on these findings, we are hoping to launch a clinical trial soon.”
Read more in Cancer Discovery.
How bone’s hardness shapes the immune battle against metastasis
Bone metastasis is one of the most dangerous and difficult-to-treat complications of cancer, yet the underlying biological mechanisms have been poorly understood.
Now, a new study from the lab of MSK immunologist Morgan Huse, PhD, and colleagues reveals the physical stiffness of our bones themselves may act as a trigger that alerts the immune system to attack invading cancer cells. The work was led by Yassmin Elbanna, a graduate student in the Gerstner Sloan Kettering Graduate School of Biomedical Sciences (GSK).
The research team found that when cancer cells interact with rigid environments like bone, they physically stiffen in response — and that this stiffening makes them more vulnerable to destruction by immune cells, particularly natural killer (NK) cells and cytotoxic T cells. In mouse models, animals lacking the ability to deploy these defenses developed widespread bone metastases, while those with intact immunity kept bone colonization largely in check.
Digging deeper, the team identified a protein called osteopontin (SPP1) as a key player in helping cancer cells adapt to — and ultimately colonize — the bone environment. Cancer cells that produce high levels of osteopontin are better at settling near bone-forming cells and establishing metastatic footholds.
An analysis of human melanoma patient data further revealed that tumors with high osteopontin and stiff cellular profiles had fewer immune cells present. This might seem paradoxical, but it actually reflects immune defenses working as expected: Because osteopontin drives the stiffening that makes cancer cells vulnerable to immune attack, those stiff cancer cells tend to be destroyed in tumors with strong immune infiltration. It is only in tumors where immune defenses are weak or absent that these stiff, osteopontin-expressing cancer cells are free to persist and accumulate.
These findings point to a process the researchers term “mechanosurveillance” — the idea that immune cells use physical cues like cell stiffness, alongside molecular signals, to detect and eliminate dangerous cancer cells. The researchers note that blocking osteopontin could represent a new strategy to enhance immune responses against bone metastasis — although the protein’s complex role in both promoting and suppressing immune activity means that therapeutically targeting it will require a nuanced approach.
Read more in Immunity.
How a telehealth tobacco treatment program helps cancer patients quit smoking
About 1 in 6 adults newly diagnosed with cancer report current smoking. Continuing to smoke after a cancer diagnosis contributes to worse treatment outcomes, faster disease progression, and a higher risk of death. For that reason, experts are looking for effective ways to help people with cancer quit tobacco.
In a randomized, controlled clinical trial conducted by a research group called ECOG-ACRIN and co-led by researchers from MSK and Mass General Brigham (MGB) in Boston, 306 people who had been diagnosed with cancer within the past four months were randomly assigned to one of two interventions to help them quit smoking:
- One group received up to 11 video counseling sessions delivered by tobacco treatment coaches that focused on motivation, coping skills, and managing cravings. They also were given free nicotine replacement patches and lozenges for up to 12 weeks.
- The other group received usual care, which consisted of receiving a letter about the National Smokers Quitline and other smoking cessation programs available from the National Cancer Institute.
After six months, 28% of patients who were provided with video counseling and nicotine replacement products had quit using tobacco, versus only 15% of the group who got usual care. In addition, among those who didn’t fully quit, the patients who received more support were much more likely to decrease their daily tobacco use.
The telehealth program benefited patients regardless of their demographic background or type of cancer. Additionally, because the study included patients who were treated at 37 community hospitals across the United States, it showed that telehealth programs can benefit those who don’t have access to treatment at a comprehensive cancer center.
“Our study shows that patients undergoing cancer treatment are much more likely to quit smoking when they receive proactive, sustained support rather than a referral alone,” says lead author Elyse R. Park, PhD, MPH, a clinical health psychologist at MGB.
“Integrating sustained tobacco treatment into community oncology settings can help close a critical gap in cancer care delivery,” adds study co-leader Jamie Ostroff, PhD, a behavioral scientist and Director of MSK’s Tobacco Treatment Program. “These practice-changing findings strongly support testing how best to scale up virtual, sustained tobacco treatment across community oncology settings so all patients with cancer can readily access evidence-based cessation support.”
Read more in the Journal of Clinical Oncology.
Atomic-level images of key phosphate transporter could inform treatment of ovarian cancer and kidney disease
Phosphate is essential for life, and the body carefully controls phosphate levels using a family of proteins called SLC34 transporters, which determine how much phosphate we absorb from food and how much our kidneys hold onto. When this system breaks down, the consequences can be serious. Too much phosphate in the blood can lead to kidney failure, heart damage, and dangerous calcium deposits throughout the body.
Despite decades of study, the physical structure of these proteins — and how that shapes their function — remained unclear. A new study from the lab of Melinda Diver, PhD, at MSK’s Structural Biology Program fills that gap. Led by postdoctoral researcher Qinyu Zhu, PhD, the team used cryo-electron microscopy (cryo-EM) to capture the first detailed 3D images of SLC34A2 — the transporter responsible for absorbing dietary phosphate — in multiple functional states.
The structures revealed that SLC34A2 has an architecture unlike any previously known protein and upended assumptions about how it does its job. Most transporters work like a revolving door: The region that grabs a molecule physically shifts to carry it across the cell membrane. SLC34A2 works differently — the part that holds phosphate stays largely in place, while a separate surrounding “gate” swings open and closed to control when phosphate can enter and when it gets locked in for transport.
The findings have direct implications for two major diseases. SLC34A2 is overexpressed in 80% to 90% of ovarian tumors and is already being targeted by experimental therapies in clinical trials. It is also a key drug target for the more than 800 million people worldwide living with chronic kidney disease. The new structures show precisely how a known inhibitor blocks the transporter — providing a roadmap for developing better drugs to fix phosphate imbalances.
Learn more in the Proceedings of the National Academy of Sciences.
Medicare Advantage patients with cancer receive optimal treatment at lower cost, study finds
Medicare Advantage plans continue to enroll a growing share of older Americans. These private insurance plans contract with the federal government to provide Medicare benefits, often with additional perks, but also with greater insurer oversight of care decisions. This raises a pressing question for oncology care: Do these plans’ efforts to control costs come at the expense of treatment quality?
A new study from MSK oncologist and health outcomes researcher Aaron Mitchell, MD, MPH, and colleagues found they do not.
The multi-institution team analyzed data from more than 35,000 patients diagnosed with cancer between 2016 and 2019. The study compared cancer treatment quality, timeliness, and cost for patients enrolled in Medicare Advantage versus traditional Medicare across 13 different cancer treatment scenarios — ranging from metastatic colon cancer to multiple myeloma to advanced prostate cancer. For each patient, the team’s analysis included the treatment they received, clinical guidelines from the National Comprehensive Cancer Network (NCCN), and Medicare reimbursement rates. This allowed researchers to assess both the clinical value and the anticipated cost of the treatment each patient received.
The study showed Medicare Advantage beneficiaries were just as likely as those with traditional Medicare to receive the optimal, guideline-recommended treatment for their cancer, and that it didn’t take longer to receive treatment — a median of 36 days versus 35 days for traditional Medicare patients. At the same time, Medicare Advantage treatments cost about 6% less, or $931 per patient.
The data further show that Advantage plans are not simply steering patients toward cheaper, lower-quality therapies — but are instead achieving savings through other mechanisms, such as using cheaper drugs that fall within guideline recommendations.
Read more in JAMA Internal Medicine.
Surgery for brain tumor-related epilepsy: How much should surgeons remove?
Tumors in the temporal lobe of the brain often cause seizures, leading to a condition called temporal-lobe epilepsy (TLE). Surgery to remove these tumors may relieve the seizures, but it’s usually not clear how much tissue should be removed. That’s because this part of the brain is important for memory and language, and removing too much can cause cognitive problems.
In a new paper, a team of experts led by Andrew Kobets, MD, MHS — a pediatric neurosurgeon who recently joined MSK and MSK Kids — reviewed past studies that had looked at this dilemma, ultimately including data from 277 patients with brain tumor–related TLE across seven different studies.
Their analysis found that complete tumor removal was the most important factor for stopping seizures. Patients whose tumors were only partially removed were more likely to continue having seizures and were at greater risk of tumor regrowth. On the other hand, removing additional brain tissue beyond the tumor itself did not consistently improve seizure outcomes.
Regarding thinking and memory, the results were mixed. Some patients showed improvements in memory and thinking skills after surgery, while others showed declines. No single surgical approach consistently produced better or worse cognitive outcomes, but a few trends emerged:
- Removing the entire hippocampus (a key memory structure in the brain) was linked to worse verbal memory outcomes.
- When tumors were in the left side of the brain, there was a higher risk of verbal memory decline after surgery.
- When tumors were located deep within the temporal lobe, patients had greater problems with memory after surgery.
“I have always been mindful about preserving long-term function by removing only the tumor and sparing as much functional surrounding brain as possible — a procedure called a lesionectomy — even though there remains a risk of postoperative seizures,” Dr. Kobets says. “Our paper showed that performing only a lesionectomy did not necessarily result in worse or persistent seizures postoperatively.”
Read more in Epilepsy & Behavior.