权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Highly selective targeted theranostics for prostate cancers

前列腺癌的高选择性靶向治疗诊断

基本信息

批准号：
10674499
负责人：
James Peter Basilion
金额：
$ 64.14万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-11 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674499
关键词：
Adverse event Affinity Androgens Animal Model Animals Antibodies Antibody-drug conjugates Antigen Targeting Antigens Antineoplastic Agents Binding Biochemical Biological Markers Cancer Etiology Canis familiaris Carcinoma Cell Death Cessation of life Chemicals Chemoresistance Clinical Clinical Trials Collection Combination Drug Therapy Combined Modality Therapy Companions Complex Cytotoxic agent Data Diagnosis Disease Dose Drug Delivery Systems Drug Synergism Drug resistance Drug toxicity Effectiveness Exhibits FOLH1 gene Future Generations Genetic Goals Hematologic Neoplasms Hormones Human Immune response Immunocompetent Immunologic Stimulation Immunologics Implant Ligands Light Local Therapy Localized Disease Location Malignant Neoplasms Malignant neoplasm of prostate Membrane Methodology Methods Microtubules Modification Molecular Weight Movement Normal Cell Normal tissue morphology Operative Surgical Procedures PUVA Photochemotherapy Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Photosensitizing Agents Physiology Prodrugs Prostate Cancer therapy Prostate carcinoma Radiation therapy Radical Prostatectomy Reactive Oxygen Species Recurrence Refractory Relapse Reporting Resistance Risk Site Solid Neoplasm Structure of base of prostate Systemic Therapy Technology Testing Therapeutic Therapeutic Effect Time Tissues Toxic effect Toxicology Trastuzumab United States Weight cancer biomarkers cancer cell cancer heterogeneity cancer therapy cell killing chemotherapy clinical application clinical efficacy clinical translation combat cost efficient design disorder risk drug clearance drug development drug efficacy efficacy evaluation efficacy study efficacy trial high risk human model humanized antibody improved irradiation men minimally invasive mouse model multimodality novel novel therapeutic intervention novel therapeutics overexpression phthalocyanine prevent prostate cancer model refractory cancer response screening serum PSA side effect small molecule systemic toxicity targeted delivery targeted imaging targeted treatment theranostics translational therapeutics treatment strategy tumor virtual

项目摘要

Abstract. Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer death in men in the United States. Although surgery and radiation therapy in patients with low risk disease appear appropriate and effective, those with high-risk localized disease almost always become hormone refractory and then rapidly progress. New treatment strategy is urgently needed for patients with high-risk localized prostate cancer, particularly an approach that considers the use of a multimodal approach and that includes both local and systemic therapies. Cytotoxic drugs are broadly used to treat hematological malignancies and solid tumors and, under certain clinical conditions, have changed the natural course of some of these diseases. While effective, due to their intrinsic mode of action, they may also cause significant off-target adverse events that could preclude their full clinical efficacy, possibly resulting in early discontinuation of medication and a consequent increased risk of tumor relapse or recurrence. Alternative approaches to both maintain the effectiveness of chemotherapeutic drugs and minimize systemic toxicity include conjugation of cytotoxic agents to humanized antibodies (also known as Antibody Drug Conjugates, ADCs). The durable clinical responses reported with brentuximab vedotin (SGN-35: Seattle Genetics/Takeda) and trastuzumab emtansine (T-DM1; Roche in partnership with ImmunoGen), which have recently obtained regulatory approval, have profoundly changed the outlook for ADC cancer therapy. These approaches, although showing strong potential, are extremely expensive, and less complex and more cost-efficient methodologies are needed. Here we describe the use of a novel ligand for prostate specific membrane antigen (PSMA, a biomarker for prostate cancer) to target a potent microtubule inhibiting agent, MMAE, and a photodynamic therapy (PDT) agent, IR700, selectively to prostate cancers. The design of this new drug molecule utilizes a prodrug approach and simultaneously delivers two drugs selectively to prostate cancer. By selective delivery of two drugs with different therapeutic mechanisms to cancer cells, improved antitumor activity with less toxicity is expected. The reduction in toxicity is expected due to anticipated drug synergy (requiring lower drug doses), site specific prodrug activation, and rapid clearance of the drug molecule, preventing off target delivery. This molecule will be developed using two animal models of prostate cancer, heterotopic human prostate cancer in mice and spontaneous prostate cancer in companion dogs. Both MMAE and IR700 therapy have been noted to stimulate immune response against cancer and we will preliminarily tested this in the immunocompetent companion dogs. Dog pathology and physiology of prostate cancer is very similar to humans and dogs are often used in drug development trials. Since efficacy trials in mice are not predictive of human results, efficacy studies in dogs will substantially encourage clinical translation of the developed agent.

摘要。前列腺癌（PCa）是最常见的恶性肿瘤，也是第二大癌症原因

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A low molecular weight multifunctional theranostic molecule for the treatment of prostate cancer.

DOI：
10.7150/thno.68715
发表时间：
2022
期刊：
Theranostics
影响因子：
12.4
作者：
Wang X;Sun R;Wang J;Li J;Walker E;Shirke A;Ramamurthy G;Shan L;Luo D;Carmon L;Basilion JP
通讯作者：
Basilion JP