Featuring findings in AML, PARP inhibitor resistance, therapeutic vaccines, triple-negative breast cancer and links between telomeres and inflammation
HOUSTON – 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. Current advances include a promising combination therapy for acute myeloid leukemia, understanding mechanisms driving resistance to PARP inhibitors, a therapeutic neoantigen vaccine to treat lung cancer, a novel treatment for triple-negative breast cancer and a new understanding of how telomeres may drive inflammatory bowel disease.
Combination therapy shows promise in mouse models of acute myeloid leukemia
Acute myeloid leukemia (AML) is a cancer that develops in the bone marrow. It is frequently treated with venetoclax, a drug that targets the protein Bcl-2 in combination with a hypomethylating agent, but often, patients develop resistance to venetoclax and then relapse. A research team led by Bing Carter, Ph.D. and Michael Andreeff, M.D, Ph.D., examined the effectiveness of combination therapy with venetoclax and SNDX-50469, a drug that inhibits another protein, menin, which is critical for a certain subset of AML cases. In their mouse model leukemia study, venetoclax alone showed no activity against the disease, but the combination showed strong anti-leukemia activity and prolonged mouse survival. Further investigation is needed to understand the combination’s mechanism of action, its appropriate dosage and its clinical effectiveness for patients. Learn more in Blood.
Identifying mechanism of resistance to PARP inhibitors
Cancer cells with mutations in certain pathways may be hypersensitive to targeted therapies against related pathways – a concept known as synthetic lethality. An example is poly ADP-ribose polymerase (PARP) inhibitors, which target DNA repair and are effective in cancers with mutations in other DNA repair genes, such as BRCA1/2. Unfortunately, cancers often develop resistance to PARP inhibitors. To identify these mechanisms of resistance, Mengfan Tang, Ph.D., and Junjie Chen, Ph.D., systematically knocked out more than 18,000 genes using CRISPR/Cas9 gene editing in cells with BRCA2 loss. They identified several genes that, when lost, led to improved survival of BRCA2-deficient cells, even when treated with PARP inhibitors. In particular, they identified loss of cyclin C (CCNC) as critical to survival of the cells, suggesting a novel therapeutic target to overcome PARP inhibitor resistance. Learn more in Nucleic Acids Research.
Therapeutic vaccine targets mutant proteins in lung cancer
Neoantigens are mutant proteins, resulting from genetic alterations in cancer cells, that can be recognized by the immune system as abnormal. MD Anderson researchers have developed therapeutic vaccines containing small neoantigen fragments, or peptides, found in a given patient’s tumor. The personalized vaccine is designed to prime the immune system to recognize and attack the tumor. A Phase I clinical trial, led by Fenge Li, M.D., Ph.D., and Gregory Lizée, Ph.D., evaluated these vaccines in patients with non-small cell lung cancer that had progressed with conventional therapies. There were minimal side effects and seven of 24 patients on the study had clinical responses – including one complete response. All responding patients had EGFR mutations, and immune monitoring suggested responses were made against several shared EGFR neoantigens. The results suggest that personalized neoantigen vaccines are safe, feasible and potentially beneficial for patients with advanced lung cancer. Learn more in the Journal for ImmunoTherapy of Cancer.
JNK signaling axis drives triple-negative breast cancer aggressiveness
Triple-negative breast cancer (TNBC) is an aggressive disease that makes up roughly 10% to 15% of breast cancer diagnoses. Because TNBCs have a poor prognosis, understanding the mechanisms that drive tumor growth and progression and finding new treatment targets are major areas of focus in breast cancer research. A team led by Naoto Ueno, M.D., Ph.D., and Takashi Semba, M.D., Ph.D., showed that the JNK/C-JUN/CCL2 signaling axis in TNBC contributes to the formation of an immunosuppressive tumor microenvironment (TME), which plays a critical role in tumor progression. The team confirmed that JNK-regulated CCL2, secreted by tumor-associated macrophages, recruits tumor-infiltrating regulatory T cells to form an immunosuppressive TME that promotes TNBC aggressiveness. The trial’s findings offer novel therapeutic strategies for TNBC by demonstrating that the immunosuppressive TME can be reversed using JNK inhibitors. A combination therapy of JNK inhibitors and immune checkpoint blockade may be effective in overcoming TNBC tumor progression. Learn more in Journal of the National Cancer Institute.
Advancing treatment options for inflammatory bowel disease
The ends of chromosomes contain long sequences of repetitive DNA, called telomeres, designed to protect the integrity of genetic information and prevent aging. Research led by Deepavali Chakravarti, Ph.D., and Ronald DePinho, M.D., previously found that telomere disruption can cause increased inflammation by activating a cellular cascade, leading to increased production of the pro-inflammatory factor IL-18. In a new study, the researchers demonstrated for the first time that this telomere-IL-18 circuit also is relevant to the development of inflammatory bowel disease (IBD). In the study, therapeutically restoring telomeres or blocking the pathways downstream of disrupted telomeres was able to reduce IL-18 production. This points to possible therapeutic strategies for treating patients with IBD who currently have limited effective therapeutic options. Learn more in Proceedings of the National Academy of Sciences.
In case you missed it
Read below to catch up on recent MD Anderson press releases across the spectrum of cancer research.
* Atezolizumab and bevacizumab show meaningful responses for malignant peritoneal mesothelioma patients
* Novel immunotherapy combination produces durable response in frontline metastatic melanoma
* MD Anderson and Hummingbird Bioscience announce strategic research collaboration to advance innovative immunotherapies
* Study identifies gut microbes associated with toxicity to combined checkpoint inhibitors in melanoma patients
Clayton R. Boldt, Ph.D.