MD Anderson Research Highlights for March 7, 2024

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 at MD Anderson offer clinical insights into a novel treatment strategy for patients with relapsed/refractory acute myeloid leukemia (AML), molecular insights into Burkitt lymphoma development, a therapeutic target to overcome venetoclax resistance in AML, preclinical activity and predictive biomarkers for an MD Anderson-developed targeted therapy, early molecular activity from an ATR inhibitor, serum tumor biomarkers to help stratify patients with appendix cancer, and a combination treatment for cancers overexpressing Aurora-A and loss of PTEN function. 

Novel antibody-drug conjugate targeting CD123 shows antileukemic activity and strong safety profile in patients with relapsed or refractory AML
Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) marked by high expression of CD123 have few effective treatment options. In a new multicenter Phase I/II trial, researchers led by Naval Daver, M.D., and Hagop Kantarjian, M.D., evaluated pivekimab sunirine, a novel CD123-targeting antibody-drug conjugate, in 91 patients with CD123+ R/R AML. This first-in-human dose-escalation and expansion study had a primary endpoint to determine the maximum tolerated dose and the recommended Phase II dose. The recommended dose was selected as 0.045 mg/kg once every three weeks. At this dose, the overall response rate was 21%, and the composite complete remission rate was 17%. The therapy was well-tolerated with manageable side effects, and patients did not experience capillary leak syndrome or severe myelosuppression, which are common with other CD123 antibody constructs. Pivekimab also is being evaluated as frontline monotherapy for blastic plasmacytoid dendritic cell neoplasm (BPDCN) in the CADENZA study and as a frontline combination with azacitidine and venetoclax in older/unfit patients with AML. Learn more in The Lancet Oncology. 

Study reveals how SMARCA4 loss contributes to Burkitt lymphoma development
SMARCA4, which normally functions as a tumor suppressor, is one of the most commonly mutated genes in human cancers, including roughly 30% of germinal center (GC)-derived Burkitt lymphomas. Germinal centers are temporarily formed zones where B cells expand, but the role of SMARCA4 in promoting lymphoma development is unclear. To provide further insights, researchers led by Michael Green, Ph.D., examined the normal role of SMARCA4 in GC B cells and how altering its function via mutation contributes to lymphoma. When functioning properly, SMARCA4 drives gene programs that allow B cells to exit the GC reaction and terminally differentiate. However, when this process is disrupted by mutation or other loss of SMARCA4 function, B cells tend to “recycle” themselves into the highly proliferative GC dark zone. When paired with over-expression of the Myc oncogene, this bias toward dark zone recycling promotes Burkitt lymphoma development. These findings also demonstrate the potential susceptibility of this cancer type to targeted therapies. Learn more in Cancer Cell. 

Interferon gamma signaling identified as key driver of venetoclax resistance in AML
Interferon gamma (IFNγ) plays several roles in immune system regulation, inflammation and tumor surveillance. However, recent research led by Hussein Abbas, M.D., Ph.D., found that patients with newly diagnosed acute myeloid leukemia (AML) have elevated levels of IFNγ, leading to an immunosuppressed bone marrow microenvironment. In a new study from the Abbas laboratory, researchers sought to characterize the role of IFNγ in the AML microenvironment. They discovered that T and NK cells are the main producers of IFNγ, suggesting that AML cells exploit this pathway to their advantage. IFNγ signaling strongly correlated with venetoclax treatment resistance in AML patient cells, and IFNγ treatment increased resistance to venetoclax therapy. Further, high IFNγ signaling was associated with poor clinical outcomes. The study uncovered new roles of IFNγ in AML immune biology, highlighting its potential as a therapeutic target. Learn more in Nature Communications.

Novel MD Anderson-developed ATR inhibitor demonstrates potent antitumor efficacy and refines understanding of ATM as predictive biomarker
ATM mutations, which affect DNA damage repair (DDR) pathways, are common in multiple cancer types. However, despite preclinical evidence that ATM mutations should be susceptible to DDR inhibitors, such as ATR inhibitors, clinical studies have produced mixed results. A new study led by Timothy Heffernan, Ph.D., Timothy Yap, M.B.B.S., Ph.D., and colleagues in MD Anderson’s Therapeutics Discovery Division reports the first disclosure and discovery of a novel ATR inhibitor, ART0380, which demonstrated potent antitumor activity in a range of preclinical models with varying degrees of ATM loss of function. To optimize biomarker selection for patients most likely to benefit, the researchers performed a comprehensive pan-cancer analysis of ATM variants in patient tumors. They characterized 10,609 variants across 8,587 tumors to understand how differences in variant type and prevalence impact tumor development. A retrospective analysis then verified these biomarkers, which could optimize patient selection and improve targeted therapy for patients with ATM loss-of-function cancers. These results have subsequently informed ongoing Phase I/II clinical trials of novel anticancer therapies in molecularly selected patient populations. Learn more in Clinical Cancer Research.   

First-in-human study of tuvusertib monotherapy demonstrates early molecular activity
ATR protein kinase inhibitors commonly are used in clinical trials to target the DNA damage repair process in cancer cells. In a first-in-human Phase I trial, researchers led by Timothy Yap, M.B.B.S., Ph.D., examined the efficacy and safety of ATR inhibitor tuvusertib in 55 patients with a wide range of biomarkers and cancer types. The researchers observed molecular responses in the predicted effective dose range, and these were more common in patients with radiological disease stabilization. Complete molecular responses were detected in patients with tumors harboring ARID1A, ATRX and DAXX mutations. Common side effects included anemia, nausea and fatigue. The recommended dose for expansion was 180 mg on a two-weeks-on, one-week-off schedule. Phase II studies are underway to further investigate tuvusertib as both monotherapy and combination therapy. Learn more in Clinical Cancer Research. 

Serum tumor markers may help oncologists stratify patients with appendix cancer
Appendix cancer is a rare and historically understudied disease. Serum tumor markers (TMs) –   specifically CEA, CA19-9 and CA125 – commonly are used to help with diagnosis, prognosis and treatment response in other cancer types, but they have not been systematically evaluated in appendix cancer. To examine if TMs would also be useful for appendix cancer, researchers led by Abdelrahman Yousef, M.D., and John Paul Shen, M.D., conducted a retrospective analysis of 1,338 patients – the largest ever cohort of this kind – to find associations between TM levels, tumor characteristics and patient outcomes. Elevated levels of any of the three TMs were associated with poorer five-year survival, and patients with elevated levels of all three TMs were at the highest risk of death. Interestingly, patients with low-grade tumors and normal CEA levels had a particularly good prognosis. The study suggests early consideration of these biomarkers could help oncologists identify which patients need treatment and determine if a treatment is working. Learn more in JAMA Network Open. 

Combination therapy triggers antitumor response in preclinical breast cancer models overexpressing Aurora-A
Aurora-A is an oncogene overexpressed in many cancer types that promotes cell proliferation, metastasis and treatment resistance. Unfortunately, therapies targeting Aurora-A are minimally successful and have unwanted side effects, highlighting a need for novel strategies. Studies have shown both pro- and anti-tumor effects of the eEF1A2 protein, which regulates protein synthesis, and its overexpression is associated with good prognosis in some breast and ovarian cancers. By examining the eEF1A2 signaling pathway, researchers led by Warapen Treekitkarnmongkol, Ph.D., Hiroshi Katayama, Ph.D., and Subrata Sen, Ph.D., showed that it promotes the degradation of Aurora-A and leads to tumor cell death. They found this antitumor effect was dependent on the interaction of eEF1A2 with the tumor suppressor PTEN. Activating this degradation pathway in combination with a targeted Aurora-A inhibitor triggered a strong antitumor response in breast cancer cells both in vitro and in vivo. This study suggests this combination has therapeutic potential for patients with cancers marked by overexpression of Aurora-A and loss of PTEN function. Learn more in Science Signaling. 

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

• Study unravels the earliest cellular genesis of lung adenocarcinoma
• MD Anderson acquires inducible switch technologies for cell therapy
• MD Anderson researchers receive over $25.5 million in CPRIT funding

Read this press release in the MD Anderson Newsroom.

 

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