MD Anderson Research Highlights for May 4, 2022

Featuring cell therapies advances, novel immunotherapy and targeted therapy combinations, a new lung cancer target, and breast cancer disparities

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recently published studies in basic, translational and clinical cancer research from MD Anderson experts. Studies include clinical advances with a new combination therapy targeting angiogenesis in platinum-resistant ovarian cancer and a promising immunotherapy combination for kidney cancer, plus laboratory studies that focus on targeting ferroptosis in specific lung cancers, developing chimeric antigen receptor (CAR) T cell therapies for blastic plasmacytoid dendritic cell neoplasms, and characterizing racial and ethnic disparities in breast cancer early detection.

Combination therapy targeting angiogenesis drivers demonstrates durable clinical activity in platinum-resistant ovarian cancer
Platinum resistance is often linked to a poor prognosis and occurs frequently in patients with advanced epithelial ovarian cancer previously treated with platinum-based chemotherapy. Targeting angiogenesis drivers — such as delta-like ligand 4 (DLL4) — may improve responses to vascular endothelial growth factor (VEGF) inhibitors and may lead to improved outcomes in patients with platinum-resistant ovarian cancer (PROC). Siqing Fu, M.D., Ph.D., and researchers evaluated the safety and efficacy of navicixizumab, which inhibits both VEGF and DLL4, in combination with paclitaxel in 44 patients with previously treated, recurrent, grade 2/3 PROC. The combination demonstrated promising clinical activity with manageable toxicity in both bevacizumab-treated and -naive patients. The overall objective response rate (ORR) was 43.2% in patients previously treated with bevacizumab, 64.3% in bevacizumab-naive patients, and 62% in patients with high angiogenesis or immune-suppressed tumor microenvironment subtypes. In patients previously treated with a PARP inhibitor, the ORR was 45%. The median duration of response was six months. The durable clinical activity of this combination suggests that navicixizumab may offer clinical benefits after other therapies for PROC, including bevacizumab, have been exhausted. Further Phase III evaluation of navicixizumab is planned. Learn more in the Journal of Clinical Oncology.

Sitravatinib plus nivolumab shows promise for advanced clear cell renal cell carcinoma
Immune checkpoint inhibitors have offered clinical benefits for some patients with advanced clear cell renal cell carcinoma (ccRCC), but many patients have limited responses to this treatment. This Phase I/II trial, led by Pavlos Msaouel, M.D., Ph.D., and Nizar Tannir, M.D., tested a combination therapy of sitravatinib — a tyrosine kinase inhibitor (TKI) — plus the anti-PD-1 immunotherapy drug nivolumab in 42 patients who had not received prior immunotherapy following disease progression on anti-angiogenic therapy. Immune monitoring studies for the clinical trial were designed, performed and analyzed by Sangeeta Goswami, M.D., Ph.D., and Padmanee Sharma, M.D., Ph.D. Sitravatinib reduced immune-suppressive myeloid cells in the tumor microenvironment, resulting in a 35.7% response rate and median progression-free survival of 11.7 months. The combination demonstrated no unexpected toxicities, and 80.1% of patients were alive after a median follow-up of 18.7 months. Additionally, patients with liver metastases showed durable responses comparable to patients without liver metastases. These results support exploring this combination therapy further to improve outcomes of anti-PD-1 therapy in advanced ccRCC. Learn more in Science Translational Medicine.

Ferroptosis protein may be novel therapeutic target in KEAP1-mutant lung cancers
Ferroptosis is an iron-dependent form of controlled cell death that is triggered by a toxic accumulation of lipid peroxides — oxidized forms of fatty acids. Targeting ferroptosis may be a viable strategy to treat cancer, but many of the mechanisms regulating ferroptosis still remain unknown. In a new study, researchers led by Pranavi Koppula, Ph.D., Guang Lei, Ph.D., and Boyi Gan, Ph.D., discovered a novel approach to targeting ferroptosis in specific lung cancers. KEAP1 mutations, found in about 16% of non-small cell lung cancers, are associated with therapy resistance and poorer outcomes. The researchers identified ferroptosis suppressor protein 1 (FSP1) as a key regulator in this process. The team demonstrated that FSP1 acts downstream of KEAP1 and its target, NRF2, to process the antioxidant ubiquinone (CoQ). FSP1 promotes resistance to ferroptosis and radiation therapy in KEAP1-mutant cancer cells. Targeting the FSP1-CoQ pathway sensitized KEAP1-mutant lung cancers to radiation therapy by inducing ferroptosis, suggesting further studies are warranted to evaluate this as a therapeutic target. Learn more in Nature Communications.

Allogeneic UCART123 cells show activity in BPDCN preclinical models
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare type of leukemia associated with poor outcomes on current therapies. Interleukin 3 receptor subunit alpha (CD123) is overexpressed in almost all cases of BPDCN, making it an attractive therapeutic target. In a new study, researchers led by Marina Konopleva, M.D., Ph.D., used UCART123, a genetically modified allogeneic T cell product manufactured from healthy donor cells, against BPDCN cells. The modified T cells express anti-CD123 chimeric antigen receptor (CAR) and the TCRa constant (TRAC) gene is inactivated using gene editing technology. UCART123 eradicated BPDCN in lab samples and resulted in long-term disease-free survival in a subset of primary patient-derived BPDCN models. These results demonstrate that allogeneic UCART123 cells have potent anti-BPDCN activity and support evaluating this treatment in future studies. Read more in Nature Communications.

Racial and ethnic disparities persist for early-stage breast cancer detection and survival
Breast cancer screening and early detection efforts have contributed to improved survival in recent decades, as breast cancer is more easily treated at early stages. But not all women have benefited equally. A study led by Shine Chang, Ph.D., and Kristin Primm, Ph.D., used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER), examining 841,975 women who were diagnosed with breast cancer between 2000 and 2017. The study found that Black, American Indian, Southeast Asian, South Asian, Pacific Islander and Hispanic women were less likely than white women to be diagnosed with early-stage breast cancer. Among those with an early-stage diagnosis, Hispanic, American Indian, Pacific Islander and Black women were more likely than white women to die from breast cancer. For women with a late-stage diagnosis, the disparity was greatest for Black women, who had 18% higher mortality than white women. The findings emphasize the need for more work to reduce breast cancer disparities. Learn more in Cancer Epidemiology, Biomarkers & Prevention.

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