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Targeted Therapy for Cancer Stem Cells
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Rama Krishna Nimmakayala, Saswati Karmakar, Garima Kaushik, Sanchita Rauth, Srikanth Barkeer, Saravanakumar Marimuthu, Moorthy P. Ponnusamy
Differential expression of Wnt signaling molecules has been implicated in a plethora of CSC’s phenotype, such as self-renewal, tumorigenesis, and dedifferentiation. This leads to the development of several targeted therapies (like monoclonal antibodies and small molecule agents) which have been tested preclinically over the year. However, no drugs have been approved for clinical usage [64]. Small molecules targeting the Wnt/β-catenin signaling can be classified into four groups: β-catenin/TCF antagonists, transcriptional coactivator modulators, Dvl binders, and other mechanism-based inhibitors [65]. Among all the small molecules, Porcupine inhibitors are the leading class, as represented by LGK974 (Novartis) [66]. Porcupine is a membrane-bound O-acetyltransferase that catalyzes the post-translational acylation of Wnt molecules and downregulation of this enzyme leads to decreased or abolished Wnt secretion [67]. In addition to small molecules, various biological agents such as OMP18R5 (also known as Vantictumab) have entered the clinical trials. OMP18R5 targets the FZD receptor and showed open label phase 1 dose escalation for solid tumors [68]. OMP-54F28 is another biologic agent and a fusion protein, which binds the Wnt ligands, thus blocking the binding of Wnt ligands with FZD receptors [68].
A synthetic anti-Frizzled antibody engineered for broadened specificity exhibits enhanced anti-tumor properties
Published in mAbs, 2018
Zvezdan Pavlovic, Jarrett J. Adams, Levi L. Blazer, Amandeep K. Gakhal, Nick Jarvik, Zachary Steinhart, Mélanie Robitaille, Keith Mascall, James Pan, Stephane Angers, Jason Moffat, Sachdev S. Sidhu
A potential approach to target cancers that depend on Wnt-β-catenin signaling is through anti-FZD antibodies (Abs) that antagonize signaling, either directly by blocking the interaction with Wnt ligands or indirectly through allosteric effects.18 An anti-FZD antagonistic Ab, known as OMP-18R5 or vantictumab, entered clinical trials after showing efficacy and safety in the treatment of multiple cancer types in mouse xenograft models.18 OMP-18R5 was derived from a phage-displayed Ab library screened against the Wnt-binding ectodomain of FZD7, but it also binds to FZD1, FZD2, FZD5 and FZD8. OMP-18R5 has been evaluated in clinical trials as a single-agent therapeutic for the treatment of solid tumors, as well as in combination with standard-of-care therapeutics for metastatic breast cancer, non-small cell lung cancer and pancreatic cancer. Clinical data in patients with solid tumors demonstrated efficacy and safety for OMP-18R5, with manageable side effects on bone turnover.19 These results indicate that targeting multiple FZDs is a promising therapeutic strategy for cancer treatment.
The biochemistry, signalling and disease relevance of RYK and other WNT-binding receptor tyrosine kinases
Published in Growth Factors, 2018
James P. Roy, Michael M. Halford, Steven A. Stacker
Therapeutic targeting of RTKs has met with substantial clinical success (Regad, 2015; Takeuchi and Ito, 2011) and drugs targeting membrane-proximal components of WNT signalling are currently being tested in clinical trials (Blagodatski et al., 2014; Driehuis & Clevers, 2017). RYK and the WNT-binding RTKs therefore represent potentially fruitful therapeutic targets. Attempts to therapeutically target distal WNT signalling components have met a number of obstacles but more success has been seen recently with the focus shifting to inhibiting WNT biosynthesis and WNT/WNT receptor interactions (Driehuis & Clevers, 2017; Kahn, 2014; Madan & Virshup, 2015). Two examples currently in clinical trials regulating WNT/FZD interactions are vantictumab and ipafricept (OncoMed Pharmaceuticals). These examples provide insight into inhibiting WNT/RYK or WNT/RTK signalling and demonstrate the feasibility of targeting WNT receptors generally. Vantictumab (OMP-18R5), a pan anti-FZD antibody blocking the WNT-binding capabilities of multiple FZD family members, has demonstrated an anti-cancer effect in colon, breast, lung, teratocarcinoma and pancreatic tumors in mice (Gurney et al., 2012). Ipafricept (OMP-54F28) is a soluble fusion of the WNT-binding cysteine-rich domain of FZD8 fused to the fragment crystallisable (Fc) portion of human IgG1 (FZD8-Fc). Ipafricept sequesters WNTs, preventing them from interacting with receptors, and reduced growth of MMTV-Wnt1 allografts, teratoma xenografts and also synergized with taxanes to reduce growth of pancreatic and ovarian patient derived xenografts (DeAlmeida et al., 2007; Fischer et al., 2017; Jimeno et al., 2017).
Pharmacotherapeutic options for pancreatic ductal adenocarcinoma
Published in Expert Opinion on Pharmacotherapy, 2022
Muhammad Sardar, Alejandro Recio-Boiles, Kabir Mody, Christian Karime, Sreenivasa R Chandana, Daruka Mahadevan, Jason Starr, Jeremy Jones, Mitesh Borad, Hani Babiker
Another potential avenue is targeting the aberrant Wnt signaling pathway implicated in PDAC pathogenesis (65% of patients) through β-catenin dependent (canonical) and β-catenin independent (non-canonical) pathways [112]. Several inhibitors targeting Wnt pathway/β catenin have been evaluated in clinical trials. Vantictumab (OMP-18R5) combined with chemotherapy showed promising results but the phase 1 trial was closed early because of high incidence of bone fractures [113]. In another phase 1b study, ipafricept (OMP-54F28) was combined with chemotherapy in 26 patients and was well tolerated with encouraging results. Most patients (81%) obtain clinical benefit and over one third (34%) had a partial response [114].