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|Ref Type||Journal Article|
|Authors||Chartier C, Raval J, Axelrod F, Bond C, Cain J, Dee-Hoskins C, Ma S, Fischer MM, Shah J, Wei J, Ji M, Lam A, Stroud M, Yen WC, Yeung P, Cancilla B, O'Young G, Wang M, Kapoun AM, Lewicki J, Hoey T, Gurney A|
|Title||Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types.|
|Date||2016 Feb 01|
|Abstract Text||Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis.|
|Molecular Profile||Treatment Approach|
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|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
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|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|RSPO3 over exp||cancer||not applicable||N/A||Preclinical - Pdx & cell culture||Emerging||In a preclinical study, advanced solid tumor cells overexpressing Rspo3 in culture and in patient-derived xenograft models demonstrated inhibition of beta-catenin activity and suppression of tumor growth when treated with RSPO3 specific antibodies, suggesting RSPO3 may be a promising therapeutic target (PMID: 26719531).||26719531|