MD Anderson Research Highlights for September 14, 2022

Featuring novel combinations and targeted therapy, surveillance testing in early-onset colorectal cancer, the link between coffee and prostate cancer survival, and blood-based ovarian cancer screening

MD Anderson News Release September 14, 2022

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts. Current advances include a new targeted therapy for small cell lung cancer, a potential combination therapy for gastric cancer, recommendations for post-surgical colonoscopies for colorectal cancer, a link between coffee consumption and survival in prostate cancer, a new blood-based metabolite panel to improve risk prediction in ovarian cancer, a combination therapy for high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia, venetoclax-based regimens as targeted therapies in acute myeloid leukemia with specific mutations, and a new target involved in skin barrier maintenance.

Adding targeted therapy improves chemotherapy responses in small cell lung cancer models
Patients with small cell lung cancer (SCLC) have limited therapeutic options and a poor prognosis. Alkylating-based chemotherapy — which causes DNA damage to prevent cell division — initially improves survival in SCLC but has toxic side effects and cancers eventually develop resistance. Newer platinum-based chemotherapy has lower toxicity, but cancers still become resistant. In a new study, Pawel Mazur, Ph.D., and colleagues performed pharmacologic and proteomics screens to identify the protein methyltransferase SMYD3 and its new substrate RNF113A as previously unrecognized mediators of resistance to alkylating agents. Using in vitro and in vivo models, the researchers demonstrated that combination therapy with a SMYD3 inhibitor and an alkylating agent effectively stopped tumor progression compared to either treatment alone. This finding has broad implications for combining SMYD3 inhibitors with alkylating-based chemotherapy to improve patient responses. Learn more in Cancer Discovery.

Combination therapy could reduce tumor growth in advanced gastric adenocarcinoma
Advanced gastric adenocarcinoma (GAC) often metastasizes in the peritoneal cavity, and peritoneal carcinomatosis (PC) treatments are mostly ineffective. Understanding the molecular signaling pathways that affect immune response in the tumor microenvironment could help improve therapeutic strategies. SOX9, a highly expressed gene in GAC and PC, is a known downstream target of oncogenic signaling pathways, but its influence on the immune system has been poorly understood. Researchers led by Shumei Song, M.D., Ph.D., used bulk RNA sequencing as well as in vitro and in vivo GAC and PC models to discover that SOX9 is involved in reducing tumor-suppressing CD8+ T cell response and increasing tumor-promoting immune cells through the LIF/LIFR signal pathway. Reducing SOX9 and inhibiting LIF/LIFR signaling significantly reduced tumor growth in vivo, suggesting this combination therapy warrants further evaluation. Learn more in Gut.

Study provides first assessment of metachronous colorectal pathology in young survivors, with potential impacts to follow-up care
Current guidelines for colorectal cancer (CRC) survivors recommend surveillance colonoscopies at one year and at 48 months after surgical resection, but these guidelines do not account for age at diagnosis. As the incidence of young-onset (diagnosed at or before age 50) CRC has risen worldwide, researchers have hypothesized that patients with spontaneous (non-hereditary) young-onset CRC could have an elevated risk for multiple, independent malignancies, known as metachronous colorectal pathology. This retrospective, single-institution study, led by Oliver Peacock, B.M.B.S., Ph.D., and Nancy You, M.D., assessed the number of high-risk premalignant lesions, secondary tumors and local recurrences found in 457 young-onset CRC survivors during post-resection surveillance. Among the metachronous colorectal pathology detected, more than half were found around one-year post-resection and another quarter before 48 months. These findings highlight the importance of post-resection surveillance for young-onset CRC patients and support consideration of an earlier timepoint for the second surveillance endoscopy in this population. Learn more in Gastroenterology.

Coffee intake and CYP1A2 AA genotype associated with longer prostate cancer survival
Coffee contains several compounds that lower inflammation, and drinking coffee may lower the risk of being diagnosed with prostate cancer. However, few studies have looked at whether coffee intake or the impact of caffeine metabolism genes can affect the risk of cancer progression among men who have been diagnosed with prostate cancer. In a study led by Justin Gregg, M.D., researchers evaluated associations between coffee intake, caffeine metabolism genotype and survival in a large, international cohort of men with prostate cancer. They showed that high coffee intake was associated with longer prostate cancer-specific survival in men who have the CYP1A2 AA genotype, which is associated with fast caffeine metabolism. These findings suggest that coffee intake may be linked to longer prostate cancer-specific survival in certain groups, though more research is needed to fully understand which men may benefit. Learn more in the European Association of Urology.

New blood-based metabolite panel improves risk prediction in ovarian cancer
Better tools are needed to distinguish between benign ovarian cysts and those that may become malignant. Current risk-assessment methods include the Risk of Ovarian Malignancy Algorithm (ROMA) and the risk of ovarian cancer algorithm (OVERA), neither of which are highly specific and can result in high false-positive rates and unnecessary procedures. To improve specificity and risk prediction, researchers led by Ehsan Irajizad, Ph.D., Chae T. Han, Ph.D., Samir Hanash, M.D., Ph.D., and Johannes F. Fahrmann, Ph.D., used sera from 101 patients with ovarian cancer and 134 patients with benign pelvic masses (BPM) to develop a blood-based panel of seven cancer-related metabolites (7MetP). The 7MetP was validated using an independent set of sera from 118 ovarian cancer cases and 56 patients with BPM. Combining 7MetP with ROMA yielded a higher positive predictive value (0.68 vs 0.52) and improved specificity for early-stage ovarian cancer compared to ROMA alone in the validation set. The 7MetP is a potential tool to complement ROMA or other risk algorithms to better inform clinical decision making and improve patient outcomes. Learn more in Clinical Cancer Research.

Azacitidine plus venetoclax shows promise in patients with high-risk MDS or CMML
Therapies beyond hypomethylating agents, such as azacitidine, are needed in high-risk myelodysplastic syndrome (MDS). In a Phase I trial led by Alexandre Bazinet, M.D., and Guillermo Garcia-Manero, M.D., researchers evaluated the use of azacitidine combined with venetoclax in 23 patients with treatment-naïve or relapsed/refractory high-risk MDS or chronic myelomonocytic leukemia (CMML) and bone marrow blasts of more than 5%. They determined the maximum tolerated dose and recommended Phase II dose of the azacitidine and venetoclax combination using a 3 + 3 study design. The combination was safe and tolerable, with an overall response rate of 87%. Based on these findings, the recommended phase 2 dose was established as azacitidine 75 mg/m2 for five days plus venetoclax 400 mg for 14 days. Learn more in The Lancet Haematology.

Study evaluates impact of venetoclax-based treatment and NPM1 mutations in IDH-mutant AML
Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations are often found with co-occurring NPM1 mutations in newly diagnosed acute myeloid leukemia (AML), which may influence treatment outcomes. Researchers led by Curtis A. Lachowiez, M.D., and Courtney DiNardo, M.D., evaluated clinical and molecular demographics, response and survival, and the impact of co-occurring NPM1 mutations in 556 patients with IDH1 or IDH2-mutated AML. Overall, more adverse outcomes were observed in IDH1-mutant vs. IDH2-mutant or NPM1-mutant AML. Important findings from this investigation demonstrated that lower-intensity venetoclax-based regimens partially evaded the harmful effects of IDH1 mutations, leading to similar overall survival observed between IDH1 mutant subsets with other IDH2 and NPM1 subsets with the incorporation of novel therapies. These results suggest that further investigations are warranted to examine molecularly targeted therapies, such as IDH1 and IDH2 inhibitors, in rational combinations for this subgroup. Learn more in other IDH2 and NPM1 subsets with the incorporation of novel therapiesAmerican Journal of Hematology.

Transcription factor regulates critical pathways involved in maintaining skin barrier
KLF5, a transcription factor broadly known to be involved in cell proliferation and regeneration, is highly expressed in skin cells but its specific functions are unknown. Ying Lyu, Ph.D., and Yejing Ge, Ph.D., sought to better understand its role in the skin by removing KLF5 from the epidermis in laboratory models. This led to several skin barrier deficiencies, and the researchers demonstrated KLF5’s importance in controlling sphingolipid metabolism and skin barrier function as well as potential involvement in stem cell function during tumorigenesis. Sphingolipids are a class of fatty acids in cell membranes that form the outermost protective barrier of skin and play a role in regulating human health and disease. Interestingly, dietary enrichment was enough to recover from these KLF5 deficiencies in vivo, highlighting KLF5 as a potential target to address skin diseases including cancer. Learn more in Genes & Development.

MD Anderson Highlights from ESMO 2022
Catch up on press releases featuring presentations from MD Anderson researchers at the European Society for Medical Oncology (ESMO) Congress 2022. More information on ESMO content from MD Anderson can be found at MDAnderson.org/ESMO. 

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High expression of SOX9 (green) and LIF (red) in gastric peritoneal metastatic tumor cells by Co-Immunofluorescent staining. Image courtesy of Shumei Song, Ph.D.