While there has been an explosion of knowledge about human carcinogenesis over the last 2 decades, unfortunately, this has not translated into the development of effective therapies for either preventing or treating the common human cancers. The goal of the Isaacs’ lab is to change this situation by translating theory into therapy for solid malignancies, particularly Prostate cancer. Presently, a series of drugs discovered in the Isaacs’ lab are undergoing clinical trials in patients with metastatic cancer. The ongoing drug discovery in the lab continues to focus upon developing agents to eliminate the cancer initiating stem cells within metastatic sites of cancer. To do this, a variety of bacterial and natural product toxins are being chemically modified to produce “prodrugs” whose cytotoxicity is selectively activated by proteases produced in high levels only by cancer cells or tumor associated blood vessel cells. In this way, these prodrugs can be given systemically to metastatic patients without un-acceptable toxicity to the host while being selectively activated to potent killing molecules within metastatic sites of cancer. Such a “Trojan Horse” approach is also being developed using allogeneic bone marrow derived Mesenchymal Stem cells which are genetically engineered to secrete “prodrugs” so that when they are infused into the patient, they selectively “home” to sites of cancers where the appropriate enzymatic activity is present to liberate the killing toxin sterilizing the cancer “neighborhood”.
Dr. Isaacs leads two distinct labs, one through the Department of Pharmacology and Molecular Sciences and one through the graduate program in Cellular and Molecular Medicine. Both labs seek to translate recent advances in theoretical knowledge regarding human carcinogenesis into therapy for solid malignancies, particularly prostate cancer.
The Pharmacology and Molecular Sciences lab focuses on developing agents to eliminate the cancer-initiating stem cells within metastatic sites of cancer. To do this, a variety of bacterial and natural product toxins are being chemically modified to produce “prodrugs” whose cytotoxicity is selectively activated by proteases produced in high levels only by cancer cells or tumor associated blood vessel cells. In this way, these prodrugs can be given systemically to metastatic patients without un-acceptable toxicity to the host while being selectively activated to potent killing molecules within metastatic sites of cancer.
The Isaacs Cellular and Molecular Medicine lab is defining the cascade of cellular and molecular events involved in Paraneoplastic cerebellar degeneration (PCD) using normal and malignant prostate cells as model systems. These studies are focused upon identifying potential therapeutic mechanisms for activating this PCD pathway as a new and more effective approach to prostate cancer therapy.
Additionally, the laboratory has an interest in addressing and understanding signaling events that play an important role in tumorogenesis and metastasis. Thus the lab is working understand androgen action, various kinase and phosphatase signaling in prostate cancer cells as well as stroma-epithelium interactions in normal prostate and prostate cancer.
Lab Website: John T. Isaacs Laboratory
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Antony L, van der Schoor F, Dalrymple SL, Isaacs JT. Androgen receptor (AR) suppresses normal human prostate epithelial cell proliferation via AR/β-catenin/TCF-4 complex inhibition of c-MYC transcription. Prostate. 2014 Aug;74(11):1118-31. doi: 10.1002/pros.22828. Epub 2014 Jun 9. PMID: 24913829 [PubMed - in process]
Doan NT, Paulsen ES, Sehgal P, Møller JV, Nissen P, Denmeade SR, Isaacs JT, Dionne CA, Christensen SB. Targeting thapsigargin towards tumors. Steroids. 2014 Jul 24. pii: S0039-128X(14)00179-2. doi: 10.1016/j.steroids.2014.07.009. [Epub ahead of print] PMID: 25065587
Brennen WN, Rosen DM, Chaux A, Netto GJ, Isaacs JT, Denmeade SR. Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer. Prostate. 2014 Jul 22. doi: 10.1002/pros.22847. [Epub ahead of print] PMID: 25053236
Brennen WN, Drake CG, Isaacs JT. Enhancement of the T-cell armamentarium as a cell-based therapy for prostate cancer. Cancer Res. 2014 Jul 1;74(13):3390-5. doi: 10.1158/0008-5472.CAN-14-0249. Epub 2014 Apr 18. PMID: 24747912
Regter S, Hedayati M, Zhang Y, Zhou H, Dalrymple S, Koch CJ, Isaacs JT, DeWeese TL. Androgen withdrawal fails to induce detectable tissue hypoxia in the rat prostate. Prostate. 2014 Jun;74(8):805-10. doi: 10.1002/pros.22803. Epub 2014 Mar 27. PMID: 24677180