Next-Gen JAK2-Inhibitors for Prostate Cancer Therapy

Men diagnosed with prostate cancer (PC) at an advanced stage or experiencing tumor recurrence after surgery require androgen deprivation (ADT) (achieved by GnRH agonist/antagonist or anti-androgens) to inhibit the androgen receptor (AR) transcription factor. A major challenge in the clinical management in this population is progression to lethal castrate-resistant PC (CRPC) despite the ADT. CRPC is consistently caused by an acquired ability of tumors to express AR and its constitutively active splice variants (AR-Vs) driving ongoing AR activity that promotes PC tumor growth and metastasis, and ultimately causes patient death.

Jak2-Stat5 signaling sustains PC cell viability and is critical for PC tumor growth. Also, Stat5 activation in PC at the time of diagnosis predicts early PC recurrence. Our investigation of the molecular targets downstream of Jak2-Stat5 signaling show that the AR gene is a critical target, and the Jak2 -Stat5 pathway suppression represents an effective strategy to deplete diverse AR and AR-V species and thereby control PCRPC growth.

We have demonstrated that the next-generation Type I Jak2 inhibitors, Pacritinib (PAC) and Fedratinib (FED) (among others), target wild-type Jak2 in cell-based assays and suppress AR mRNA and protein levels in PC. Importantly, Wt-Jak2 targeting Jak2-inhibitors induce robust death of PC cells, in PC xenograft tumors and clinical patient-derived PCs ex vivo in explant cultures. In contrast, the first-generation Jak2-inhibitor, Ruxolitinib (RUXO), which failed in clinical trials in PC, displayed no suppression of the WtJak2-Stat5-AR axis in PC or PC cell viability.

Key Advantages

  • A new class of androgen receptor antagonists for prostate cancer therapy
  • Represents a significant market opportunity
  • Depletion of Androgen Receptor (AR) levels in PC provides a therapy option for hormone-sensitive and hormone-resistant prostate cancer.

Website

https://www.mcw.edu/-/media/MCW/Departments/Office-of-Technology-Development/OTD-Available-Technologies-No-2068-Next-Gen-JAK2-Inhibitors-Prostate-Cancer-Therapy.pdf

Contact Information

MCW Office of Technology Development: https://www.mcw.edu/departments/technology-development

Name: Kevin Boggs, Ph.D., MBA

Title: Director

Phone: (414) 955-4381

Email: kpboggs@mcw.edu