Revere Pharma Announces Publication of Research that Elaborates Role of Rac1 in Prostate Cancer
Research conducted by Dr. Erik Goka and published in Molecular Cancer Therapeutics demonstrates that Rac1 inhibition can attenuate the growth and survival of prostate cancer cells
Boston, Mass. — Revere Pharmaceuticals, an emerging biopharmaceutical company developing small molecule drugs targeting key signaling proteins to treat cancer and other disease, announced the publication of research results demonstrating the central role of Rac1 signaling in the growth and survival of prostate cancer cells. The article, titled “Hormone dependent prostate cancers are dependent on Rac signaling for growth and survival,” is based on research conducted by Erik Goka, PhD, the company’s head of biology, and published in Molecular Cancer Therapeutics, a peer-reviewed publication of the American Association of Cancer Research. The research was conducted under the direction of Dr. Marc Lippman, a preeminent cancer researcher at Georgetown University, who is a member of Revere’s board of directors.
“Dr. Goka’s recently published work demonstrates the pivotal role of Rac1 signaling in castrate resistant prostate cancer and the promise of targeting Rac1 to advance the treatment of this disease,” said Jedd Levine, MD, Chief Medical Officer Revere Pharmaceuticals.
The published research demonstrated that Rac1 dysregulation resulted in cancer-driving mechanisms of enhanced cellular proliferation, motility and viability in prostate cancer. Moreover, the work revealed a link between Rac1 signaling and androgen receptor gene expression, indicating a potential role for Rac1 inhibition in combination with conventional androgen receptor antagonists.
This paper builds upon a substantial body of Rac1 research published by a research team headed by Drs. Goka and Lippman. Over the last several years, this team has elucidated the mechanism by which Rac1 activation promotes the growth of multiple tumor types. They further showed that pharmacologic inhibition of Rac1 effectively inhibited tumor growth in vivo. Key findings from recent publications include the following:
- “Rac Signaling Drives Clear Cell Renal Carcinoma Tumor Growth by Priming the Tumor Microenviornment for an Angiogenic Switch” Mol. Cancer Ther. (2020).
In this study, a Rac1 inhibitor was found to suppress the pro-angiogenic growth factors VEGF, TSP-1 and CXCL16, block angiogenesis and inhibit CC renal carcinoma growth in vivo.
- “Rac1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer” Mol. Cancer Ther. (2019).
Rac1b, a constitutively active splice variant of Rac1, was found to be overexpressed in colorectal cancer with the highest levels in metastatic disease. Furthermore, Rac1b was shown to activate the pro-survival NF-kB pathway which leads to resistance to standard-of-care chemotherapy (5-FU and Oxaliplatin). Rac1 inhibition was found to sensitize colorectal cancer to chemotherapy.
- “Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression” Oncogene (2015).
The authors showed for the first time the role of HACE1 in breast cancer progression and why it correlates to poor patient outcomes. HACE1 was found to reduce levels of activated Rac1 by targeting (GTP-bound) Rac1 for ubiquitin mediated protein degradation.
“It is exciting to be a part of this important research that expands our understanding of the role of Rac1 signaling in cancer progression,” said Dr. Goka, Revere Senior Director of Biology and lead author of the study. “I look forward to translating these findings into new medicines to treat patients with the Revere team.”
About Rho GTPases
Rho GTPases are a diverse group of signaling proteins, including Rac1 and Cdc42, which serve as molecular ‘on-off’ switches because of their ability to bind to the guanosine triphosphate (GTP) nucleotide and hydrolyze it to guanosine diphosphate (GDP). Activity of these proteins switch between the inactive GDP-bound form and the active GTP-bound form which recruits other downstream effector proteins to promote many critical cancer processes, including cell growth, migration, invasion, and angiogenesis. Dysregulation of Rac1 or Cdc42 is implicated in multiple cancer types including lung, breast, prostate, colorectal, and gastric cancer and is commonly associated with resistance to chemotherapy and other targeted cancer therapeutics. Rho GTPase dysregulation has also been implicated in chronic kidney disease and viral infections such as SARS CoV2.
About Revere Pharmaceuticals
Revere Pharmaceuticals is a biopharmaceutical company developing small molecule drugs targeting the Ras-homologous (Rho) family GTPases, molecular switches that are central to cancer progression and other disease processes. Based on a deep understanding of how to balance the active and inactive forms of the GTPase, the company has built a pipeline of novel small molecules that target Rac1, select Rac1 variants and CDC42. The company is headquartered in Boston, Massachusetts. For more information, please visit www.reverepharma.com.