MD Anderson Research Highlights

Featuring a combination treatment for gastric cancer, positive ADC results in colorectal cancer, and a new understanding of liver regeneration

The University of Texas MD Anderson Cancer Center’s Research Highlights showcases the latest breakthroughs in cancer care, research, and prevention. These advances are made possible through seamless collaboration between MD Anderson’s world-leading clinicians and scientists, bringing discoveries from the lab to the clinic and back.

Targeting an enzyme as part of combination therapy disrupts gastric cancer progression

Many patients with gastric cancer have metastatic disease at the time of diagnosis, highlighting a need to identify pathways that control malignant progression. Researchers led by Pawel Mazur identified a previously unrecognized lysine methyltransferase, SMYD5, that is highly expressed in patients with gastric cancer and is associated with poorer outcomes.

The researchers found that SMYD5 specifically methylates the rpL40 protein, which remodels a particular region on ribosomes, resulting in increased new protein formation and cancer growth. Inhibiting SMYD5 in patient-derived and genetically engineered lab models blocked cancer cell growth and sensitized them to targeted therapy treatment. Further, SMYD5 inhibition combined with targeted therapy and chimeric antigen receptor (CAR) T cell therapy effectively eliminated aggressive gastric cancer in vivo, supporting the therapeutic potential of this combination.

ADC shows promising results in treating HER2+ metastatic colorectal cancer

HER2 is overexpressed in some colorectal cancers, contributing to poor prognosis, brain metastases and resistance to anti-EGFR therapies. Findings from the DESTINY-CRC01 study suggested that the HER2-targeted antibody-drug conjugate (ADC), trastuzumab deruxtecan, might benefit patients with HER2 positive, RAS-wild-type metastatic colorectal cancer.

In the Phase II DESTINY-CRC02 trial, led by Kanwal Raghav, researchers evaluated the safety and efficacy of two doses of trastuzumab deruxtecan in 122 patients from multiple countries, all of whom had undergone chemotherapy and targeted treatments.

The results showed that the lower dose had a 37.8% objective response rate, compared to 27.5% with the higher dose. Both doses were generally well tolerated, but the lower dose had fewer severe side effects. This study led to Food and Drug Administration approval of trastuzumab deruxtecan for HER2+ metastatic colorectal cancer, underscoring the ADC as an effective treatment option for this challenging cancer type.

LIFR regulates cholesterol-driven process for liver regeneration

The liver is the only human organ that can fully regenerate, even after as much as 70% of it has been removed. New liver tissue can grow back to match the original organ’s size and functionality without turning into cancer, but how it does so remains unclear. White blood cells known as neutrophils recently have been implicated in this process, but the pathway involved in releasing neutrophils from the bone marrow after liver injury is poorly understood.

Researchers led by Li Ma, uncovered new pathways orchestrated by leukemia inhibitory factor receptor (LIFR) to facilitate the regeneration process.

When the liver is damaged, LIFR from hepatocytes – the most common liver cell type – promotes the production and secretion of cholesterol and the CXCL1 protein. While CXCL1 promotes the release of bone marrow neutrophils to the liver, cholesterol stimulates neutrophils to produce hepatocyte growth factor to induce hepatocyte proliferation. This novel role for cholesterol in the regenerative process of the liver could have potential clinical implications.

Novel biomarker can stratify patients with large cell neuroendocrine carcinoma

Patients with large cell neuroendocrine carcinoma (LCNEC) have few treatment options and poor prognoses, highlighting the need to identify more effective therapeutic targets. By examining molecular data from preclinical models and patients, researchers led by Carl Gay uncovered two distinct types of LCNEC based on the presence of the transcription factor YAP1. YAP1-high and YAP1-low LCNEC have different genetic and gene expression features, underscoring the need for individually tailored treatments.

YAP1-low tumors resemble small cell lung cancers (SCLC), including several proteins targeted by emerging SCLC treatments. Conversely, YAP1-high tumors exhibit features suggesting they would benefit from immunotherapies and targeted therapies most associated with non-small cell lung cancers. These results suggest that YAP1 status could guide the application, or even development, of personalized treatments for patients with LCNEC.

Novel BCL2 inhibitor shows promise in relapsed CLL

Patients with newly diagnosed chronic lymphocytic leukemia (CLL) respond well to the B cell lymphoma 2 (BCL2) inhibitor, venetoclax, as their initial treatment, but an increasing number of patients will relapse. Many of these relapsed patients retain sensitivity to BCL2 inhibitors and also have elevated levels of other anti-apoptotic proteins, such as B-cell lymphoma extra-large (BCLXL).

To improve patient outcomes, researchers led by Deepa Sampath examined the mechanism of action and activity of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition, in preclinical studies. Researchers observed reduction in tumor burden, survival advantages and low platelet toxicity. These results warrant further investigation and evaluation of the novel treatment in venetoclax-responsive and relapsed CLL.

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