Modulation of host intrinsic immunity to reduce prostate cancer disparity

调节宿主内在免疫以减少前列腺癌差异

• 批准号: 10246377
• 负责人: Dev Karan
• 金额: $ 30.79万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246377
• 关键词: Affect; African American; Agonist; Antigens; Antitumor Response; Attenuated; Cancer Cell Growth; Cancer Etiology; Cancer Prognosis; Castration; Caucasians; Cell Cycle Regulation; Cells; Cessation of life; Combined Modality Therapy; Cytidine Deaminase Inhibitor; DNA Damage; DNA Methylation; DNA Modification Methylases; Data; Death Rate; Decitabine; Deoxycytidine; Disease; Dose; Dysmyelopoietic Syndromes; Enzymes; Epigenetic Process; Ethnic Origin; Event; FDA approved; Frequencies; Genes; Genetic; Goals; Growth; Human; Immune; Immune response; Immunity; Immunocompetent; Immunologics; Immunotherapeutic agent; Immunotherapy; Incidence; Intervention; Malignant neoplasm of prostate; Minority Groups; Modification; Mus; Mutation; Neoplasm Metastasis; Outcome; Patients; Pharmacology; Population; Prostatic Neoplasms; Public Health; Race; Regimen; Resistance; Risk; Safety; Socioeconomic Factors; Structure of base of prostate; Testing; Tetrahydrouridine; Time; Toll-like receptors; Translating; Treatment Efficacy; Treatment Protocols; Tumor Burden; Tumor Immunity; United States; Uridine; Vaccine Therapy; Vaccines; absorption; analog; base; cancer health disparity; cancer stem cell; cancer survival; cancer type; castration resistant prostate cancer; combinatorial; cytotoxicity; differential expression; epigenetic therapy; immunoregulation; in vivo; innovation; men; mortality; mouse model; neoplastic cell; novel; prostate cancer cell; prostate cancer cell line; prostate cancer model; public health relevance; racial disparity; reconstitution; therapeutic target; therapeutic vaccine; transgenic adenocarcinoma of mouse prostate; treatment response; tumor; tumor growth; tumorigenic

 DESCRIPTION (provided by applicant): Cancer health disparities represent a major public health concern in the United States. Even when socioeconomic factors are accounted for, minority populations have higher overall incidence rates and worse outcomes than the overall population. Prostate cancer is one such disease with higher incidence and death rates in African American (AA) men than Caucasians. Although socioeconomic factors may be blamed to a certain extent, it is appreciated that the genetic composition makes AA men more susceptible to aggressive prostate cancer. Genetic and epigenetic changes are known as tumorigenic drivers because epigenetic editing precludes mounting of host antitumor response necessary for tumor cell clearance. DNA methylation, catalyzed by DNA methyltransferase (DNMT), is the best-characterized epigenetic modification in prostate cancer, and racial disparities in DNA methylation are associated with cancer prognosis and survival. Therefore, targeting of DNMT to reverse epigenetic alterations is an appealing therapeutic target, and vital to reduce the observed prostate cancer outcome gaps among AA men and Caucasians. The deoxycytidine analogue decitabine is unique in that it can be repositioned for non-cytotoxic depletion of DNMT. We characterized a low dose of decitabine with its increased absorption in the presence of tetrahydrouridine (THU). Combination of THU with decitabine changes its pharmacology, and facilitates non-cytotoxic DNMT1 depletion. We demonstrated that the THU-decitabine combination significantly inhibits the growth of TRAMP-C2 prostate tumors in immune competent mice, and the addition of CpG immunotherapy further enhanced antitumor immunity. Based on our strong preliminary data, we hypothesize that THU-decitabine directed epigenetic therapy revitalize the host intrinsic immunity and augment vaccine-induced antitumor response. Since DNA methylation is prevalent and relates to greater risk in AAs, DNMT depletion will invigorate the immune response of tumor-bearing host, providing an opportunity to immunotherapy inducing robust antitumor immunity. We will test the combination of THU-decitabine directed DNMT depletion, immune modulation and therapeutic vaccine to determine 1) the effect of epigenetic editing on prostate cancer cell growth in murine models; and 2) the effector mechanism of THU-decitabine guided vaccine- induced antigen-specific antitumor immunity in complete regression of early and advanced castration-resistant prostate cancer. This project is novel because the concept of a non-toxic THU-decitabine combination with immunotherapy has not been tested in any cancer type. This combinatorial approach will significantly attenuate the growth of aggressive prostate cancer as often presented in AA men, and may represent a novel treatment to reduce prostate cancer disparity.



项目成果

Formulation of the bivalent prostate cancer vaccine with surgifoam elicits antigen-specific effector T cells in PSA-transgenic mice.

使用 surgifoam 配制二价前列腺癌疫苗可在 PSA 转基因小鼠中引发抗原特异性效应 T 细胞。

• DOI: 10.1016/j.vaccine.2017.09.037
• 发表时间: 2017
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Karan,Dev

DNA Methyltransferase 1 Targeting Using Guadecitabine Inhibits Prostate Cancer Growth by an Apoptosis-Independent Pathway.

DNA甲基转移酶1使用瓜杜发可以通过凋亡独立的途径抑制前列腺癌的生长。

• DOI: 10.3390/cancers15102763
• 发表时间: 2023-05-15
• 期刊: Cancers
• 影响因子: 5.2

Reply to "Contextualizing racial associations in prostate cancer to expose structural causes".

回复“前列腺癌中的种族关联以揭示结构性原因”。

• DOI: 10.1002/cncr.35167
• 发表时间: 2024
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Karan,Dev;Wick,Jo;Dubey,Seema;Kumar-Sinha,Chandan;Siddiqui,Javed;Kunju,LakshmiP;Iczkowski,KennethA;Chinnaiyan,ArulM
• 通讯作者: Chinnaiyan,ArulM

CCL23 in Balancing the Act of Endoplasmic Reticulum Stress and Antitumor Immunity in Hepatocellular Carcinoma.

• DOI: 10.3389/fonc.2021.727583
• 发表时间: 2021
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Karan D

Circulatory MIC-1 as a Determinant of Prostate Cancer Racial Disparity.

• DOI: 10.3390/cancers12103033
• 发表时间: 2020-10-18
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Karan D;Wick J;Dubey S;Tawfik O;Van Veldhuizen P
• 通讯作者: Van Veldhuizen P