Progress in Process
Recent peer-reviewed research papers by SWCRF scientists showcase new findings with potential for novel cancer therapies.
The months following the Samuel Waxman Cancer Research Foundation’s scientific review and symposium in May have been fruitful ones for several SWCRF-funded researchers who have had their theories published in research journals in a wide range of cancer categories. The investigators are reporting findings that move forward their projects and have the potential for therapeutic applications at the clinical level.
Uncovering a New Therapeutic Target for Leukemia in Children with Down syndrome
|John Crispino, Ph.D.|
In the area of blood cancer, SWCRF investigator John Crispino, Ph.D. of the Robert H. Lurie Comprehensive Cancer at Northwestern Medicine published with collaborators in the Journal of Experimental Medicine a paper regarding a gene on chromosome 21 called DYRK1A that contributes to the onset of acute lymphoblastic leukemia. Patients with Down syndrome have three copies of chromosome 21 in their cells. They’re also 20 times more likely to contract childhood B-cell acute lymphoblastic leukemia than the general population, making that chromosome an important avenue for researching the genetic basis of the cancer.
Over-production of immature lymphocytes is a hallmark of acute lymphoblastic leukemia and Dr. Crispino’s work involving lab mice lacked DYRK1A in blood cells. They saw that two types of white blood cells called B and T lymphocytes were severely blocked from developing without the gene. The scientists also found evidence that DYRK1A is normally responsible for regulating cell cycle progression in those lymphocytes. These results suggest the gene is a strong target for therapy in this form of leukemia.
Targeting the Spread of Triple-Negative Breast Cancer
SWCRF’s funded team investigating Triple-Negative Breast Cancer (TNBC), Samuel Waxman, M.D., Ming-Ming Zhou, Ph.D. and Eduardo Farias, Ph.D. of the Icahn School of Medicine at Mount Sinai, and Arthur Zelent, Ph.D. of the University of Miami, were published in Molecular Cancer Therapeutics for identifying avermectins – compounds with insecticidal properties -- as potential inhibitors of TNBC metastasis.
TNBC is a particularly aggressive breast cancer subtype characterized by the lack of estrogen, progesterone and HER2 receptors. It accounts for 10 percent to 20 percent of breast cancer cases, is prevalent among African-Americans, Latinas and Ashkenazi women and has a high incidence of recurrence.
The researchers previously targeted mutated TNBC epigenetics using a peptide that modulated genes associated with epithelial mesenchymal transition (EMT), a genetic process that promotes the spread of cancer cells. Their follow-up research identified two compounds that could serve as inhibitor agents, selamectin and ivermectin, both of which induced expression of the tumor suppressor gene CDH1 and the transcription factor ESR1 in human and mouse TNBC cells, restoring the cells’ sensitivity to the breast cancer drug tamoxifen.
Targeting residual Multiple Myeloma Cells After Bortezomib Treatment
|Julio Aguirre-Ghiso, Ph.D.|
Tumor dormancy expert Julio Aguirre-Ghiso, Ph.D. of the Icahn School of Medicine at Mount Sinai published with collaborators in BMC Cancer results from a study on the multiple myeloma cells that remain after patients are treated with the proteasome inhibitor bortezomib. Dr. Aguirre-Ghiso and his colleagues tested the effect of a demethylating agent, 5-Azacytidine, to boost the killing and growth suppression of multiple myeloma cells in response to bortezomib and inhibited the GRP78/BiP protein using a toxin that provoked the self-destruction of the surviving multiple myeloma cells. The study showed that a low dose of the 5-Azacytidine stabilized the dormancy in the myeloma cells after bortezomib treatment. Further, they showed that a high level of the GRP78 protein in cancer cells isolated from patients correlated with progressive disease. The results indicated that a combination of 5-Azacytidine and bortezomib might be a new therapeutic course for delaying the recurrence of multiple myeloma and targeting Grp78 might eradicate even dormant cancer cells.
Tracking an Oncoprotein’s Role in a Rare and Deadly Cancer
|Christopher French, M.D.|
Researchers at Brigham & Women’s Hospital, led by SWCRF investigator Christopher French, M. D., published findings in Genes & Development describing how the BRD4-NUT oncoprotein takes over large areas of chromatin – known as megadomains -- inside cells and drives abnormal transcription that causes NUT midline carcinoma (NMC), a rare cancer with a dismal prognosis. NMC is an epithelial cancer that occurs in the middle area of the body, such as the nose, mouth, trachea and upper airways. The cure rate is less than five percent and the average survival from time of diagnosis is less than one year.
It is likely that the disease may be underdiagnosed given its symptoms are similar to those of other cancers and there is a limited number of laboratories with NMC expertise. Dr. French’s work is the first to identify the role of cancer-causing genes such as TP63, MYC and MED24 within the megadomains that drive the growth of NMC. The investigation also showed that the BET inhibitor JQ1 was effective in diminishing the BRD4NUT megadomains, offering a potential new therapeutic approach.
Advocating for Targeted Therapeutic Approaches to Primary Liver Cancer
|Josep M. Llovet, M.D.|
SWCRF researcher Josep M. Llovet, M.D., who leads the renowned liver cancer research program at the Icahn School of Medicine at Mount Sinai, published a paper in Nature Reviews advocating for the application of biomarker-based clinical trials for potential therapies for hepatocellular carcinoma (HCC), which accounts for up to 90 percent of all primary liver cancers in the world.
Dr. Llovet’s paper analyzed potential factors affecting the outcomes of several Phase III clinical trials that failed to improve on the results of the kinase inhibitor sorafenib, the standard treatment for HCC. Dr. Llovet and his co-authors note that recent advances in knowledge of the human genome have led to the identification of commonly mutated genes in HCC that can be directly targeted or through epigenetic modifiers and microRNAs. Furthermore, the results of ongoing clinical studies that incorporate predictive biomarkers into trials for potential HCC drugs are eagerly awaited.
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