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SMURF-Therapeutics, Inc.

Smurf2 was discovered in the EL-DEIRY LAB at Brown University as a cellular protein that binds and degrades HIF1alpha (and HIF2alpha) in cancer cells treated with CDK4/6 inhibitor.

Thus, drugs that boost Smurf2 levels in cancer cells and its binding to HIF proteins will have anti-cancer efficacy since HIF promotes tumor blood vessel formation, cancer cell invasion and metastases, and its inhibition is associated with reduced tumor growth and metastasis. 

The classical understanding of how cells respond and adapt to hypoxia by inducing HIF proteins was awarded the Nobel Prize in Physiology or Medicine in 2019, including for work showing that the Von Hippel Lindau (VHL) tumor suppressor protein targets HIF for degradation and that this is blocked by oxygen modifications on HIF proteins. In kidney cancer the VHL tumor suppressor is frequently mutated leading to unregulated HIF proteins that drive cancer. In Von Hippel Lindau disease, VHL mutations that are inherited predispose affected individuals to develop kidney cancer and cerebellar hemangiomas (vascular tumors due to high levels of HIF proteins). 

HIF proteins induce VEGF and Erythropoietin to promote wound healing and red blood cell production. In the field of cancer, bevacizumab (Avastin), the first anti-angiogenic drug that targets VEGF, was developed by Genentech (now Roche) and has several billion dollars in sales annually. VEGF normally promotes wound healing so that in patients who do not have cancer, an increase in VEGF in a wound accelerates wound healing. In kidney disease, there is anemia due to reduced erythropoietin production. Thus, with the discovery of Smurf2 as a regulator of HIF proteins, our goal is to use small molecules to increase Smurf2 as a cancer therapeutic strategy and to lower Smurf2 (or block its activity), in patients without cancer, as a strategy to promote wound healing or treat anemia of chronic disease.



Inhibition of Smurf2 E3 ubiquitin ligase by heclin and its analogues enhances HIF-1α expression and transcriptional activity in normoxia or hypoxia

Anti‑cancer efficacy including Rb‑defcient tumors and VHL‑independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90

Integrating Molecular Biomarker Inputs Into Development and Use of Clinical Cancer Therapeutics

Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase

miR-6883 downregulates HIF1α in colorectal and breast cancer cells

Hyperprogression of a mismatch repair-deficient colon cancer in a humanized mouse model following administration of immune checkpoint inhibitor pembrolizumab.

A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs.

Strategies to sensitize cancer cells to immunotherapy.

Targeting apoptosis in cancer therapy.

The current state of molecular testing in the treatment of patients with solid tumors, 2019.

miR-6883 Family miRNAs Target CDK4/6 to Induce G1 Phase Cell-Cycle Arrest in Colon Cancer Cells.

Application of 3D tumoroid systems to define immune and cytotoxic therapeutic responses based on tumoroid and tissue slice culture molecular signatures.

Circulating tumor cells: silent predictors of metastasis.

Tumor Evolution, Heterogeneity, and Therapy for Our Patients With Advanced Cancer: How Far Have We Come?

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia.

HIF-1 signaling in drug resistance to chemotherapy.

CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth.

Hyperspectral imaging: a non-invasive method of imaging melanoma lesions in a patient with stage IV melanoma, being treated with a RAF inhibitor.

Overcoming hypoxia-induced apoptotic resistance through combinatorial inhibition of GSK-3β and CDK1.

Reduced cell death, invasive and angiogenic features conferred by BRCA1-deficiency in mammary epithelial cells transformed with H-Ras.

Noninvasive vascular imaging in fluorescent tumors using multispectral unmixing.

Microarray analysis of p53-dependent gene expression in response to hypoxia and DNA damage.

Effects of low confluency, serum starvation and hypoxia on the side population of cancer cell lines.

Differentiation of vascular and non-vascular skin spectral signatures using in vivo hyperspectral radiometric imaging: implications for monitoring angiogenesis.

Imaging and oncologic drug development.

Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis.

Modulation of TRAIL-induced tumor cell apoptosis in a hypoxic environment.

Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth.

Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein.

The administration schedule of cyclin-dependent kinase inhibitor gene therapy and etoposide chemotherapy is a major determinant of cytotoxicity.

Role of oncogenes in resistance and killing by cancer therapeutic agents.

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