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DNA Methylation Inhibitor Therapy for Testicular Cancer

DNA 甲基化抑制剂治疗睾丸癌

基本信息

批准号：
9919539
负责人：
MICHAEL J SPINELLA
金额：
$ 44.93万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919539
关键词：
Acute Androgens Cardiovascular system Cell Culture Techniques Cells Cessation of life Chromatin Cisplatin Clinical Common Carcinoma Coronary heart disease Cytotoxic Chemotherapy DNA DNA Damage DNA Methylation DNMT3B gene Deoxycytidine Disease Dose Double-Stranded RNA Embryonal Carcinoma Embryonal Carcinoma Cell Epigenetic Process Family Future Gene Activation Gene Expression Genes Genetic Goals Human Hypersensitivity Hypogonadism Immune checkpoint inhibitor Immunologic Surveillance In Vitro Infertility Intervention Life Link Malignant Neoplasms Malignant neoplasm of testis Mediating Methylation Modeling Molecular Myelosuppression Pathway interactions Patient-Focused Outcomes Patients Pharmacogenetics Pharmacogenomics Phase Phase I Clinical Trials Platinum Prodrugs Prognostic Marker Publishing Quality of life Refractory Refractory Disease Relapse Renal function Research Resistance Respiratory physiology Risk Salvage Therapy Sampling Signal Transduction Solid Neoplasm Structure of primordial sex cell Survivors TP53 gene Testicular Germ Cell Tumor Testing Therapeutic Trials Therapy trial Toxic effect Tumor Suppressor Genes Work Xenograft Model Xenograft procedure acute toxicity adduct base cancer cell chemotherapy clinical investigation cohort cost cytotoxicity demethylation design epigenetic therapy epigenome gene repression genome wide methylation high risk improved improved outcome in vivo inhibitor/antagonist innovation knock-down neoplastic cell neurotoxicity novel outcome forecast phase I trial pluripotency prognostic promoter psychologic rare cancer response response biomarker side effect standard of care stem cells tumor young man

项目摘要

Testicular germ cell tumors (TGCTs) are the most common carcinomas of young men. Currently available cisplatin-based cytotoxic therapies result in substantial acute and life-long side effects that greatly impact quality of life. In addition, 15- 20% of cases are refractory or relapse despite cisplatin therapy and are fatal. There are currently no reliable prognostic makers to predict non-responders. This application is based on our novel observations that pluripotent embryonal carcinoma (EC), the stem cells of TGCTs, are exquisitely sensitive to low dose demethylation treatment with 5-aza deoxycytidine (5-aza) and that low dose 5-aza is effective in mediating promoter demethylation and p53 target gene expression. The 5-aza hypersensitivity extends to cisplatin resistant EC and 5-aza pretreatment can restore cisplatin sensitivity to refractory cells. Together, this work provides the rationale for our recently initiated and highly promising phase I clinical trial to study the novel 5-aza prodrug SGI-110 in cisplatin refractory TGCT patients. The objective of this proposal is to define the precise molecular mechanism(s) of TGCT hypersensitivity to DNA methylation therapy in order to provide the rationale and biomarkers of response to support future epigenetic-based therapy trials to treat testicular cancer and other solid tumors. The hypothesis is that TGCTs, even those refractory to standard platinum based chemotherapy, are hypersensitive to low dose treatment with DNA methylation inhibitors and can also be resensitized to cisplatin based-therapy. We also hypothesize that specific epigenetic features of pluripotent TGCT cells make them vulnerable to DNA methylation inhibitor therapy and that at least some of these features could apply to rare cancer initiating cells in somatic solid tumors. Our studies will use a combination of cell culture, human xenograft and PDX models, and primary patient samples including samples from the ongoing Phase I trial of SGI-110 in cisplatin refractory TGCTs. Aim 1 will determine whether 5-aza/SGI-100 and cisplatin sensitivity in TGCTs is due to specific alterations in genome-wide methylation and chromatin accessibility. Aim 2 will determine whether the mechanism of 5-aza/SGI-110 hypersensitivity in TGCT cells is due to hyperactivation of immune surveillance pathways. Aim 3 will validate these findings in PDX and orthotopic xenograft models and in primary TGCTs including tumors from an ongoing SGI-110 phase I therapeutic trial. This project teams molecular and epigenetic biologists with an esteemed clinically oriented research group that will set the stage for interventions targeting the TGCT epigenome and guide and impact the design of future clinical investigations.

睾丸生殖细胞肿瘤（tgct）是年轻男性最常见的癌症。目前可用的以顺铂为基础