Fox Chase Cancer Center Background
Pancreatic ductal adenocarcinoma (PDAC) affects 44,000 individuals yearly in the United States. Almost universally, this cancer is lethal, with very limited efficacy of chemotherapy. The carcinogenesis and progression of PDAC is universally driven by “undruggable” mutations in oncogenes. Mutations in the oncogenic c-Myc and its amplification in human cancers have been the focus of the many studies. However, an effective way to cure c-MYC-dependent cancers has not been uncovered. Therefore, transformative new therapies are urgently needed for these devastating malignancies.
Researchers from Fox Chase Cancer Center have developed a novel system for determining drug sensitivity of a tumor with c-Myc gene amplification and/or overexpression. Personalized patient derived xenograft (PDX) mouse models of pancreatic and ovarian cancers with high level of c-Myc oncogene amplification and with genomic heterogeneity and drug sensitivity of original tumors were used to determine the sensitivity of these tumors to natural compound triptolide. Based on the results, it was proposed to use c-Myc as a biomarker for patients with wide range of cancers that carry this genetic abnormality. Comparison of the “patient” c-MYC data (levels of mRNA and protein) with the reference values defines the tumor sensitivity score as a result. Furthermore, the degree of sensitivity score determines whether the tumor is resistant to the chemotherapeutic agent or to its particular doses and estimates whether the patient will respond positively to such treatment.
This novel monitoring system allows estimating sensitivity to the treatment with triptolide, its analogues and prodrugs, and also agents that target RNA polymerase II driven transcription. By selecting patients with the tumors which are sensitive to triptolide, based on c-Myc, lower dosages of triptolide can be successfully used with reduced side effects. Thus, this monitoring system alters the normal course of cancer treatment by providing a checkpoint and indicates whether or not that patient will appropriately respond to the therapy, improve the safety of the treatment, or determine whether a different therapeutic regimen may be proposed to the patient.
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