MD Anderson Research Highlights for April 19, 2023

HOUSTON ― 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.

Recent developments include effective combination therapies for patients with BRAF^V600E mutations, an approach to identify cancer biomarkers in extracellular vesicles, therapeutic strategies for improving treatment responses in non-small cell lung cancer, and a novel combination therapy to overcome treatment resistance in a subset of patients with acute myeloid leukemia.

Final data from Phase II ROAR trial continue to signal promising results
Beyond melanoma, BRAF^V600E alterations are seen in multiple cancer types. The final results of the Phase II Rare Oncology Agnostic Research (ROAR) basket trial highlight the efficacy and safety of the targeted therapy combination dabrafenib plus trametinib for these patients. The trial, led by Vivek Subbiah, M.D., comprised cancers with BRAF^V600E aberrations, including anaplastic thyroid, biliary tract, gastrointestinal stromal tumor, adenocarcinoma of the small intestine, high- and low-grade glioma, hairy cell leukemia and multiple myeloma. The single gastrointestinal stromal tumor patient did not respond; the overall response rate (ORR) for high-grade gliomas was 33%, and all other groups had an ORR of at least 50%. A pooled analysis of this trial data, together with data from the NCI MATCH trial and a pediatric trial, led to the tissue agnostic FDA approval of the combination for patients with unresectable metastatic solid tumors with BRAF^V600E mutations, representing a milestone in precision medicine. ROAR previously led to FDA approval in anaplastic thyroid cancer and promising activity in biliary tract cancer and gliomas, leading to inclusion in National Comprehensive Cancer Network guidelines. Learn more in Nature Medicine.

Study identifies approach to identify cancer-derived miRNA using extracellular vesicles
Extracellular vesicles (EVs) carry genetic and biological cargo between cells and are present in body fluids. Their contents could include valuable cancer biomarkers, such as microRNAs (miRNAs), but there are no well-defined methods for differentiating EVs derived from cancer versus normal cells. Researchers led by Honami Naora, Ph.D., identified that the glycoprotein CD147 is expressed on EVs that lack tetraspanins, the most commonly used surface markers of EVs. The study showed a higher prevalence of CD147-positive EVs, but not tetraspanin-positive EVs, in patients with renal and ovarian cancers compared to healthy individuals. The researchers discovered that CD147-positive EVs are derived predominantly from cancer cells and have substantially higher miRNA content than tetraspanin-positive EVs. Additionally, miRNAs isolated using CD147 immunocapture closely reflect tumor miRNA signatures, highlighting a viable approach for detecting cancer-derived miRNA in multiple disease sites. Learn more in the Journal of Extracellular Vesicles.  

STAT6 blockade enhances antitumor response in preclinical NSCLC models
Patients with metastatic non-small cell lung cancer (NSCLC) often develop resistance to radiation and immunotherapy, partly due to a tumor microenvironment that recruits immunosuppressive M2 tumor-associated macrophages (TAM). Because M2 TAMs are known to be activated by the STAT6 signal pathway, researchers led by James Welsh, M.D., targeted STAT6 with an antisense oligonucleotide (ASO) in combination with low and high doses of radiation in NSCLC models. This combination reduced M2 TAM infiltration and induced a strong antitumor response, including slower tumor growth, decreased lung metastases and longer survival. The results suggest that blocking STAT6 with the ASO inhibits M2 polarization, favoring a shift towards antitumor M1 TAM activity, which enhances the immune response. This study highlights the potential of adding a STAT6 ASO to current immunotherapy and radiation options to improve outcomes for patients with immune-resistant NSCLC. Learn more in Cancer Immunology Research.

Preclinical study shows targeted therapy and chemotherapy combination effective as first-line treatment in BRAF^V600e-mutant colorectal cancer Many patients with metastatic colorectal cancer (mCRC) harboring BRAF^V600E mutations – the most common mutation in mCRC – may develop resistance to chemotherapy, but they respond well to the BRAF and EGFR inhibitors encorafenib and cetuximab as a second-line treatment. However, these targeted therapies have not been tested in patients with untreated BRAF^V600E-mutant mCRC. To improve first-line treatment options, Scott Kopetz, M.D., Ph.D., and colleagues examined various combinations of encorafenib and cetuximab with sequential chemotherapy in vivo using BRAF^V600E-mutant mCRC lab models. The study highlighted signaling pathways involved in the development of chemotherapy resistance and supported the combination of cytotoxic chemotherapy with molecular targeted therapy as a viable therapeutic strategy for first-line treatment to improve patient outcomes. Learn more in Clinical Cancer Research. 

Novel combination therapy shows efficacy in preclinical models of mutant AML
Patients with acute myeloid leukemia (AML) expressing mutant NPM1 (mtNPM1) – the most common genetic alteration – usually have a favorable prognosis after treatments with a menin inhibitor (MI) and chemotherapy. However, most elderly patients and those with co-mutations in FLT3 end up relapsing and having worse outcomes. This underscores the need to understand the mechanisms behind treatment resistance and to develop more effective therapeutic strategies. Researchers led by Christopher Mill, Ph.D., and Kapil Bhalla, M.D., used RNA sequencing in CRISPR-edited AML models to identify several pan-HDAC inhibitors and a WEE1 inhibitor with potential therapeutic value. Treatment with a WEE1 inhibitor (adavosertib) or pan-HDAC inhibitor (panobinostat) was effective in combination with a MI in vitro and in vivo, highlighting these combinations as viable options to improve patient outcomes. Learn more in Leukemia. 

MD Anderson at AACR 2023
Read below for highlights from MD Anderson at the American Association for Cancer Research (AACR) Annual Meeting 2023. More information can be found at MDAnderson.org/AACR.

• Single-cell study uncovers distinct immunosuppressive tumor microenvironment in brain metastases from kidney cancer
• Early trial results show benefits of FGFR inhibitors and PARP/ATR inhibitor combinations in multiple tumor types
• Mutations in three key genes associated with poor outcomes in lung cancer patients treated with KRAS G12C inhibitors
• Novel allogeneic CAR T cell therapy delivers promising early results in patients with metastatic clear cell renal cell carcinoma
• YAP/TEAD inhibitor VT3989 is well tolerated and shows antitumor activity in advanced mesothelioma and NF2-mutant cancers
• Lung cancer outcomes significantly improved with immunotherapy-based treatment given before and after surgery
• MD Anderson Research Highlights AACR 2023 Special Edition
• Andy Futreal and Helen Piwnica-Worms elected Fellows of the AACR Academy 

In case you missed it
Read below to catch up on recent MD Anderson press releases.

• Metastasis-directed radiation therapy plus hormone therapy improves progression-free survival for men with advanced prostate cancer
• MD Anderson applauds NCI’s National Cancer Plan
• Novel immunotherapy delivery approach safe and beneficial for some melanoma patients with leptomeningeal disease

 

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