MSK Research Highlights, June 25, 2024

New research from Memorial Sloan Kettering Cancer Center (MSK) helped develop a machine-learning tool to help find cancer cells that remain after surgery; led to Food and Drug Administration approval for CAR T cell therapy against mantle cell lymphoma; tested a liquid biopsy approach that shows promise in detecting lung cancer; found checkpoint inhibitors were effective against endometrial and ovarian cancers with DNA-repair deficiency; and shed new light on mTOR’s role in metabolic enzyme degradation.

Machine-learning tool helps find cancer that remains after surgery

Many people who initially receive surgical treatment for solid tumors eventually have their cancer come back. A big reason why is minimal residual disease (MRD): small numbers of cancer cells that stay in the body and eventually form new tumors. MSK has led many efforts to detect MRD in recent years, including focusing on blood tests called liquid biopsies that are able to pick up low levels of tumor DNA in the blood. This can indicate the presence of cancer that remains after treatment.

In a new study, a team of scientists led by MSK breast oncologist Adam Widman, MD, and Dan Landau, MD, PhD, of Weill Cornell Medicine analyzed  a new liquid biopsy tool named MRD-EDGE. The researchers showed that this technology, developed by Dr. Widman and Dr. Landau, was able to find MRD after surgery in several cancer types — including colorectal cancer, lung cancer, breast cancer, and melanoma. MRD-EDGE uses machine learning to detect cancer mutations called single nucleotide variants and copy number variants. And the approach is able to find traces of cancer at levels that are too low to be picked up by other liquid biopsy tests. The investigators will continue to study the technology, which they say could help to determine which patients are not likely to benefit from chemotherapy after surgery, so that it is given only to patients who need it. Read more in Nature Medicine.

CAR T therapy proves effective for mantle cell lymphoma

On May 30, the United States Food and Drug Administration (FDA) announced the approval of lisocabtagene maraleucel (Breyanzi®), a chimeric antigen receptor (CAR) T cell therapy for adults with relapsed or refractory mantle cell lymphoma who have received at least two lines of systemic therapy. Mantle cell lymphoma is a rare, aggressive form of non-Hodgkin lymphoma. The treatment targets a molecule on the surface of blood cancer cells called CD19. The approval was based on a study led by hematologist oncologist M. Lia Palomba, MD and showed that of 88 patients who received the therapy, the objective response rate was 83% — with 72% having a complete response. The median duration of response was nearly 16 months, and progression-free survival was just over 15 months. Dr. Palomba also contributed to the FDA approval of lisocabtagene maraleucel for relapsed or refractory follicular lymphoma, which was announced on May 15. Read more in the Journal of Clinical Oncology.

Machine learning-enabled liquid biopsy test may help close the lung cancer screening gap

Low-dose computed tomography (CT) is an approved screening test for lung cancer in high-risk populations. Yet many people who are likely to benefit choose not to have these scans. Investigators are looking for other screening methods. They include liquid biopsies that test patients’ blood for minute fragments of tumor DNA. In a recent study, a multicenter team that included researchers from MSK looked at one such liquid biopsy test.

The primary objective of the study was to train and validate a blood test that can detect fragments of DNA linked to genome-wide changes associated with lung cancer.  Blood samples from people confirmed to have lung cancer were used to train the test, which then applied machine learning to predict the likelihood of cancer, based on DNA fragments found. 

The investigators concluded the test has the ability to identify who is most likely to benefit from low dose CT. They report that the sensitivity of the test is 80%, with a negative predictive value of 99.8%, meaning that a patient with a test result of “not elevated” has a 2 in 1,000 chance of actually having a lung cancer. By using this test, the study concludes that the chance of finding a lung cancer using a follow-up low-dose CT is increased by 5.5 times in individuals with an “elevated” versus “not elevated” result.

“We are excited by these promising results and hope that the deployment of this assay and others like it will save many millions of lives through the earlier detection of cancer,” says MSK physician-scientist Luke Pike, MD, DPhil, the paper’s senior author. Read more in Cancer Discovery. 

Checkpoint inhibitors effective against endometrial and ovarian cancers with DNA-repair deficiency

Immunotherapy drugs called checkpoint inhibitors can be effective against cancers with a genetic abnormality called mismatch repair (MMR) deficiency or microsatellite instability (MSI). This flaw leaves cells with an inability to repair mistakes in the DNA. MSK gynecologic medical oncologist Claire Friedman, MD, led a clinical trial testing the checkpoint inhibitor nivolumab (Opdivo®) in people with endometrial (uterine) or ovarian cancers that are either MMR-deficient or otherwise have a high number of genetic mutations.

Results from the phase 2 trial in 35 patients show that nivolumab is effective in these cancers, with 59% responding to the drug, meaning their tumors shrank or disappeared. Two years after treatment, 65% had not had their disease return or progress. In addition, researchers were able to identify genetic and molecular biomarkers — in both the tumor and the tumor microenvironment — that indicated how well a patient would respond to the treatment. Knowing these biomarkers could help guide patient selection for future trials. Read more in Nature Medicine.

Study sheds new light on mTOR’s role in metabolic enzyme degradation

Human cells have to orchestrate more than 20,000 proteins to maintain healthy growth and survival. As conditions change, cells adapt by making new proteins and breaking down existing proteins. One common stressor that cells experience is a change in the availability of nutrients. Mammalian target of rapamycin (mTOR) is a protein that senses these changes and, when nutrients are scarce, can trigger a process known as autophagy to recycle amino acids and make their components available for reuse. It has been unclear, however, how nutrient stress affects protein degradation beyond autophagy — which only accounts for a portion of protein turnover. 

A new study from the lab of chemical biologist Heeseon An, PhD, at the Sloan Kettering Institute, found that mTOR also controls the breakdown of certain key metabolic enzymes via the ubiquitin pathway. The stability of one enzyme in particular, called HMGCS1, is tightly regulated by the mTOR-Ubiquitin pathway. This controls the abundance of HMGCS1 in cells and affects cellular sterol metabolism and cell proliferation. The study found that when mTOR is inhibited, a protein complex called CTLH E3 ligase induces the degradation of HMGCS1, while this degradation is inhibited when mTOR signaling is active. Overall, the study adds a new understanding of how mTOR regulates cellular metabolism: controlling the stability of key metabolic enzymes via the ubiquitin system. Read more in Molecular Cell.