Itraconazole as a Noncastrating Treatment for Biochemically Recurrent Prostate Cancer: A Phase 2 Study

Lee, Mina; Hong, Haemin; Kim, Won; Zhang, Li; Friedlander, Terence W.; Fong, Lawrence; Lin, Amy; Small, Eric J.; Wei, Xiao X.; Rodvelt, Tammy J.; Miralda, Brigid; Stocksdale, Brian; Ryan, Charles J.; Aggarwal, Rahul

doi:10.1016/j.clgc.2018.09.013

Cited by 22 publications

(6 citation statements)

References 16 publications

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“…ITZ is a known Hh inhibitor (Kim et al, 2010), which could explain its effect in RCC-FG2 cells. Unlike other azole antifungal drugs, ITZ does not block gonadal and adrenal steroidogenesis, suggesting it may potentially have value as a non-castrating treatment approach, but clinical studies of ITZ in biochemically recurrent prostate cancer, showed that ITZ had only a modest effect (Lee et al, 2019). These data is in agreement with our observation that ITZ on its own had little cytotoxicity with only a very modest effect observed at higher concentrations (Figure 2A).…”

Section: Discussionsupporting

confidence: 89%

Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer

et al. 2022

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Docetaxel (DTX) was the first chemotherapeutic agent to demonstrate significant efficacy in the treatment of men with metastatic castration-resistant prostate cancer. However, response to DTX is generally short-lived, and relapse eventually occurs due to emergence of drug-resistance. We previously established two DTX-resistant prostate cancer cell lines, LNCaPR and C4-2BR, derived from the androgen‐dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line, respectively. Using an unbiased drug screen, we identify itraconazole (ITZ), an oral antifungal drug, as a compound that can efficiently re-sensitize drug-resistant LNCaPR and C4-2BR prostate cancer cells to DTX treatment. ITZ can re-sensitize multiple DTX-resistant cell models, not only in prostate cancer derived cells, such as PC-3 and DU145, but also in docetaxel-resistant breast cancer cells. This effect is dependent on expression of ATP-binding cassette (ABC) transporter protein ABCB1, also known as P-glycoprotein (P-gp). Molecular modeling of ITZ bound to ABCB1, indicates that ITZ binds tightly to the inward-facing form of ABCB1 thereby inhibiting the transport of DTX. Our results suggest that ITZ may provide a feasible approach to re-sensitization of DTX resistant cells, which would add to the life-prolonging effects of DTX in men with metastatic castration-resistant prostate cancer.

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Section: Discussionsupporting

confidence: 89%

Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer

et al. 2022

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“…Currently, 2 HHIs, vismodegib (Genentech Inc, South San Francisco, CA) and sonidegib (Sun Pharmaceutical Industries, Inc, Cranbury, NJ), are approved by the US Food and Drug Administration (FDA) for use in advanced BCC [34,35]. Itraconazole (Janssen Pharmaceuticals, Inc., Titusville, NJ) [36], an antifungal agent, inhibits HH signaling in cancer and is under investigation for clinical efficacy in several tumor types [37,38]. Patidegib was granted Orphan Drug and Breakthrough Therapy Designation by the FDA as a topical agent for the treatment of BCCNS [39,40].…”

Section: Preclinical Development Of Hedgehog Inhibitors For the Treatmentioning

confidence: 99%

Hedgehog signaling inhibitors in solid and hematological cancers

Cortes

Gutzmer

Kieran

et al. 2019

Cancer Treatment Reviews

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Background: The hedgehog signaling pathway is normally tightly regulated. Mutations in hedgehog pathway components may lead to abnormal activation. Aberrantly activated hedgehog signaling plays a major role in the development of solid and hematological cancer. In recent years, inhibitors have been developed that attenuate hedgehog signaling; 2 have been approved for use in basal cell carcinoma (BCC), while others are under development or in clinical trials. The aim of this review is to provide an overview of known hedgehog inhibitors (HHIs) and their potential for the treatment of hematological cancers and solid tumors beyond BCC. Design: Published literature was searched to identify articles relating to HHIs in noncutaneous cancer. Both preclinical and clinical research articles were included. In addition, relevant clinical trial results were identified from www.clinicaltrials.gov. Information on the pharmacology of HHIs is also included. Results: HHIs show activity in a variety of solid and hematological cancers. In preclinical studies, HHIs demonstrated efficacy in pancreatic cancer, rhabdomyosarcoma, breast cancer, and acute myeloid leukemia (AML). In clinical studies, HHIs showed activity in medulloblastoma, as well as prostate, pancreatic, and hematological cancers. Current clinical trials testing the efficacy of HHIs are underway for prostate, pancreatic, and breast cancers, as well as multiple myeloma and AML. Conclusions: As clinical trial results become available, it will be possible to discern which additional tumor types are suited to HHI mono-or combination therapy with other anticancer agents. The latter strategy may be useful for delaying or overcoming drug resistance. Dysregulated hedgehog signaling and the development of cancer The HH signaling pathway is normally tightly regulated; however, dysregulation due to mutations in Smo or Ptch1 plays a major role in

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“… Itraconazole Another promising drug with anti-angiogenic activity is the antifungal itraconazole [ 142 ]. It has been examined in a phase II randomized trial, including 46 patients with chemotherapy-naïve mCRPC, receiving either low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole [ 143 ]. There were no PSA response in the low-dose arm, a PSA decrease was seen in 14% of men in the high-dose arm, and 62% of participants changed to a favorable CTC count (<5 CTCs/7.5 mL blood) after itraconazole treatment.…”

Section: Anti-angiogenic Agents In Prostate Cancermentioning

confidence: 99%

Angiogenesis and Anti-Angiogenic Treatment in Prostate Cancer: Mechanisms of Action and Molecular Targets

Ioannidou

Moschetta

Shah

et al. 2021

IJMS

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Prostate cancer (PC) is the most common cancer in men and the second leading cause of cancer-related death worldwide. Many therapeutic advances over the last two decades have led to an improvement in the survival of patients with metastatic PC, yet the majority of these patients still succumb to their disease. Antiagiogenic therapies have shown substantial benefits for many types of cancer but only a marginal benefit for PC. Ongoing clinical trials investigate antiangiogenic monotherapies or combination therapies. Despite the important role of angiogenesis in PC, clinical trials in refractory castration-resistant PC (CRPC) have demonstrated increased toxicity with no clinical benefit. A better understanding of the mechanism of angiogenesis may help to understand the failure of trials, possibly leading to the development of new targeted anti-angiogenic therapies in PC. These could include the identification of specific subsets of patients who might benefit from these therapeutic strategies. This paper provides a comprehensive review of the pathways involved in the angiogenesis, the chemotherapeutic agents with antiangiogenic activity, the available studies on anti-angiogenic agents and the potential mechanisms of resistance.

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Itraconazole as a Noncastrating Treatment for Biochemically Recurrent Prostate Cancer: A Phase 2 Study

Cited by 22 publications

References 16 publications

Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer

Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer

Hedgehog signaling inhibitors in solid and hematological cancers

Angiogenesis and Anti-Angiogenic Treatment in Prostate Cancer: Mechanisms of Action and Molecular Targets

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