Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related death. It is of vital importance to develop new strategies for prostate cancer therapy. PSMA (prostate-specific membrane antigen) is specifically expressed in prostate cancer and the neovasculature of certain cancer types, thus is considered to be an ideal target for cancer therapy. In our previous study, we have obtained a PSMA-specific single-chain variable fragment (scFv), named gy1,...
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The growing cost of medical care worldwide, particularly in oncology, has incentivized researchers and physicians to repurpose clinically used drugs to alleviate the financial burden of drug development and offer potential new therapeutics. Recent works have demonstrated anticancer properties of the FDA-approved drug ribavirin, a synthetic guanosine analogue and antiviral molecule used over the past four decades for the treatment of hepatitis C. The efficacy of ribavirin in cancer has been explored...
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Targeting of extrinsic apoptosis pathway by TNF-related apoptosis-inducing ligand (TRAIL) is an attractive approach for cancer therapy. However, two TRAIL drug candidates failed in clinical trials due to lack of efficacy. We identified 17-hydroxy wortmannin (17-HW) in a drug repurposing screen that resensitized TRAIL's response in the resistant colon cancer cells. The deficiency of caspase-8 in drug-resistant cells along with defects in apoptotic cell death was corrected by 17-HW, an inhibitor of...
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Alpha-emitters can be pharmacologically delivered for irradiation of single cancer cells, but cellular lethality could be further enhanced by targeting alpha-emitters directly to the nucleus. PARP-1 is a druggable protein in the nucleus that is overexpressed in neuroblastoma compared with normal tissues and is associated with decreased survival in high-risk patients. To exploit this, we have functionalized a PARP inhibitor (PARPi) with an alpha-emitter astatine-211. This approach offers enhanced...
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Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. In Saudi Arabia, colorectal cancer is more aggressive and presents at younger age, warranting new treatment strategies. Role of TGFβ/Smad4 signaling pathway in initiation and progression of colorectal cancer is well documented. This study examined the role of TGFβ/Smad4 signaling pathway in a large cohort of Saudi patients with colorectal cancer, followed by in vitro analysis to dissect the dual role of TGFβ on inducing...
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NEDD8-activating enzyme (NAE) is an essential E1 enzyme of the NEDD8 conjugation (neddylation) pathway, which controls cancer cell growth and survival through activation of cullin-RING ubiquitin ligase complexes (CRL). In this study, we describe the preclinical profile of a novel, highly potent, and selective NAE inhibitor, TAS4464. TAS4464 selectively inhibited NAE relative to the other E1s UAE and SAE. TAS4464 treatment inhibited cullin neddylation and subsequently induced the accumulation of CRL...
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The DNA damage response (DDR) kinases ATR, Chk1, and Wee1 play vital roles in the response to replication stress and in maintaining cancer genomic stability. Inhibitors of these kinases are currently under clinical investigation. Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are aggressive lymphomas whose clinical outcome is still largely unsatisfactory. These cell lymphoma subtypes are highly dependent on both Chk1 and Wee1 for survival. We investigated the activity of the...
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The oncogenic transcription factor FOXM1 has been previously shown to play a critical role in carcinogenesis by inducing cellular proliferation in multiple cancer types. A small-molecule compound, Robert Costa Memorial drug-1 (RCM-1), has been recently identified from high-throughput screen as an inhibitor of FOXM1 in vitro and in mouse model of allergen-mediated lung inflammation. In the present study, we examined antitumor activities of RCM-1 using tumor models. Treatment with RCM-1 inhibited tumor...
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IL15 and costimulatory receptors of the tumor necrosis superfamily (TNFRSF) have shown great potential to support and drive an antitumor immune response. However, their efficacy as monotherapy is limited. Here, we present the development of a novel format for a trifunctional antibody-fusion protein that combines and focuses the activity of IL15/TNFSF-ligand in a targeting-mediated manner to the tumor site. The previously reported format consisted of a tumor-directed antibody (scFv), IL15 linked to...
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Prostate cancer remains among the leading causes of cancer-related deaths in men. Patients with aggressive disease typically undergo hormone deprivation therapy. Although treatment is initially very successful, these men commonly progress to lethal, castration-resistant prostate cancer (CRPC) in 2 to 3 years. Standard therapies for CRPC include second-generation antiandrogens, which prolong patient lifespan by only several months. It is imperative to advance our understanding of the mechanisms leading...
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Proteolysis-targeting chimeras (PROTAC) are bifunctional molecules that hijack endogenous E3 ubiquitin ligases to induce ubiquitination and subsequent degradation of protein of interest. Recently, it has been shown that PROTACs with robust in vitro and in vivo activities and, in some cases, drug-like pharmaceutical properties can be generated using small-molecule ligands for the E3 ligases VHL and CRBN. These findings stoked tremendous enthusiasm on using PROTACs for therapeutics development. Innate...
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The RNA-Binding Protein HuR Confers Oxaliplatin Resistance of Colorectal Cancer By Upregulating CDC6
Human antigen R (HuR) is an RNA-binding protein that posttranscriptionally regulates many cancer-trait genes. CDC6, a central regulator of DNA replication, is regulated by HuR. In this study, we investigated the role of HuR in colorectal cancer tumorigenesis and oxaliplatin (L-OHP) resistance, as well as the underlying mechanisms involving CDC6. We detected increased HuR and CDC6 expression, along with a positive correlation between the two in human colorectal cancer tissues. HuR overexpression increased...
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FGFR1 was recently shown to be activated as part of a compensatory response to prolonged treatment with the MEK inhibitor trametinib in several KRAS-mutant lung and pancreatic cancer cell lines. We hypothesize that other receptor tyrosine kinases (RTK) are also feedback-activated in this context. Herein, we profile a large panel of KRAS-mutant cancer cell lines for the contribution of RTKs to the feedback activation of phospho-MEK following MEK inhibition, using an SHP2 inhibitor (SHP099) that blocks...
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