Scott J Weir

University of Kansas, Lawrence, Kansas, United States

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Publications (19)123.32 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):4214-4214. DOI:10.1158/1538-7445.AM2015-4214 · 9.33 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):1895-1895. DOI:10.1158/1538-7445.AM2015-1895 · 9.33 Impact Factor
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    ABSTRACT: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. It arises from loss of intestinal epithelial homeostasis and hyperproliferation of the crypt epithelium. In order to further understand the pathogenesis of CRC it is important to further understand the factors regulating intestinal epithelial proliferation and more specifically, regulation of the intestinal epithelial stem cell compartment. Here, we investigated the role of the RNA binding protein RBM3 in stem cell homeostasis in colorectal cancers. Using a doxycycline (Dox) inducible RBM3 overexpressing cell lines HCT 116 and DLD-1, we measured changes in side population (SP) cells that have high xenobiotic efflux capacity and increased capacity for self-renewal. In both cell lines, RBM3 induction showed significant increases in the percentage of side population cells. Additionally, we observed increases in spheroid formation and in cells expressing DCLK1, LGR5 and CD44(Hi) . As the Wnt/β-catenin signaling pathway is important for both physiologic and cancer stem cells, we next investigated the effects of RBM3 overexpression on β-catenin activity. RBM3 overexpression increased levels of nuclear β-catenin as well as TCF/LEF transcriptional activity. In addition, there was inactivation of GSK3β leading to decreased β-catenin phosphorylation. Pharmacologic inhibition of GSK3β using (2'Z,3'E)-6-Bromoindirubin-3'-oxime (BIO) also recapitulates the RBM3 induced β-catenin activity. In conclusion, we see that RNA binding protein RBM3 induces stemness in colorectal cancer cells through a mechanism involving suppression of GSK3β activity thereby enhancing β-catenin signaling. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 08/2015; DOI:10.1002/mc.22404 · 4.81 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):1893-1893. DOI:10.1158/1538-7445.AM2015-1893 · 9.33 Impact Factor
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    ABSTRACT: This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax(®)) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. Twenty-one patients with peritoneal malignancies received Nanotax(®) in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50-275 mg/m(2)) of Cremophor-free Nanotax(®) were administered intraperitoneally for one to six cycles (every 28 days). Intraperitoneal (IP) administration of Nanotax(®) did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration-time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450-2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax(®) IP treatment. Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax(®) provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.
    Cancer Chemotherapy and Pharmacology 04/2015; 75(5). DOI:10.1007/s00280-015-2737-4 · 2.77 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-343. DOI:10.1016/S0016-5085(15)31144-6 · 16.72 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-63-S-64. DOI:10.1016/S0016-5085(15)30222-5 · 16.72 Impact Factor
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    ABSTRACT: Gastrointestinal Stromal Tumor (GIST) is a rare and therefore often neglected disease. Introduction of the kinase inhibitor, imatinib mesylate (IM) radically improved the clinical response of patients with GIST; however, its effects are often short-lived, with GISTs demonstrating a median time to progression of approximately two years. Although many investigational drugs, approved first for other cancers, have been subsequently evaluated for the management of GIST, few have greatly impacted the overall survival of patients with advance disease. We employed a novel, focused, drug repurposing effort for GIST including IM-resistant GIST evaluating a large library of FDA-approved drugs regardless of current indication. As a result of the drug repurposing screen, we identified eight FDA-approved drugs including fludarabine phosphate (F-AMP) that showed synergy with and/or overcame resistance to IM. F-AMP induces DNA damage, annexin V and caspase 3/7 activities as the cytotoxic effects on GIST cells including IM-resistant GIST cells. F-AMP and IM combination treatment showed greater inhibition of GIST cell proliferation when compared to IM alone and F-AMP alone. Successful in vivo experiments confirmed the combination of IM with F-AMP enhanced the antitumor effects compared to IM alone. Our results identified F-AMP as a promising, repurposed drug therapy for the treatment of GISTs, with potential to be administered in combination with IM or for treatment of IM-refractory tumors.
    Molecular Cancer Therapeutics 08/2014; 13(10). DOI:10.1158/1535-7163.MCT-14-0043 · 5.68 Impact Factor
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    ABSTRACT: The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine and conducted the first-in-human phase I study of this drug in patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5-80 mg/m(2) oral ciclopirox olamine once daily for five days in 21-day treatment cycles. Pharmacokinetic and pharmacodynamic companion studies were performed in a subset of patients. Following definition of the half-life of ciclopirox olamine, an additional cohort was enrolled and treated with 80 mg/m(2) ciclopirox olamine four times daily. Adverse events and clinical response were monitored throughout the trial. Twenty-three patients received study treatment. Ciclopirox was rapidly absorbed and cleared with a short half-life. Plasma concentrations of an inactive ciclopirox glucuronide metabolite were greater than those of ciclopirox. Repression of survivin expression was observed in peripheral blood cells isolated from patients treated once daily with ciclopirox olamine at doses greater than 10 mg/m(2) , demonstrating biological activity of the drug. Dose-limiting gastrointestinal toxicities were observed in patients receiving 80 mg/m(2) four times daily, and no dose limiting toxicity was observed at 40 mg/m(2) once daily. Hematologic improvement was observed in two patients. Once-daily dosing of oral ciclopirox olamine was well tolerated in patients with relapsed or refractory hematologic malignancies, and further optimization of dosing regimens is warranted in this patient population.
    American Journal of Hematology 04/2014; 89(4). DOI:10.1002/ajh.23640 · 3.80 Impact Factor
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    ABSTRACT: Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25-30 million people in the U.S. alone. Given the costs associated with the discovery, development and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, "drug repurposing" or "repositioning", has emerged as an alternative to the traditional drug development process. In this study we screened 796 FDA-approved drugs and found that two of these compounds, auranofin and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs including imatinib-resistant cells. One of the most notable drug hits, auranofin (Ridaura®), an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis (RA), was found to inhibit thioredoxin reductase (TrxR) activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anti-cancer activity associated with auranofin was independent of IM resistant status, but was closely related to the endogenous and inducible levels of ROS, therefore is prior to IM response. Coupled with the fact auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for GIST patients, particularly in those suffering from imatinib-resistant and recurrent forms of this disease.
    Molecular Cancer Therapeutics 05/2013; 12(7). DOI:10.1158/1535-7163.MCT-12-0968 · 5.68 Impact Factor
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    ABSTRACT: A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound.
    Journal of Medicinal Chemistry 05/2012; 55(12):5878-86. DOI:10.1021/jm300330b · 5.45 Impact Factor
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    ABSTRACT: Despite advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. It is a rapidly invasive, metastatic tumor that is resistant to standard therapies. The phosphatidylinositol-3-kinase/Akt and mTOR signaling pathways are frequently dysregulated in pancreatic cancer. Gemcitabine is the mainstay treatment for metastatic pancreatic cancer. P276 is a novel CDK inhibitor that induces G(2)/M arrest and inhibits tumor growth in vivo models. Here, we determined that P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis, a mechanism-mediated through inhibition of Akt-mTOR signaling. In vitro, the combination of P276 and gemcitabine resulted in a dose- and time-dependent inhibition of proliferation and colony formation of pancreatic cancer cells but not with normal pancreatic ductal cells. This combination also induced apoptosis, as seen by activated caspase-3 and increased Bax/Bcl2 ratio. Gene profiling studies showed that this combination downregulated Akt-mTOR signaling pathway, which was confirmed by Western blot analyses. There was also a downregulation of VEGF and interleukin-8 expression suggesting effects on angiogenesis pathway. In vivo, intraperitoneal administration of the P276-Gem combination significantly suppressed the growth of pancreatic cancer tumor xenografts. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, again suggesting an effect on angiogenesis. Taken together, these data suggest that P276-Gem combination is a novel potent therapeutic agent that can target the Akt-mTOR signaling pathway to inhibit both tumor growth and angiogenesis.
    Molecular Cancer Therapeutics 04/2012; 11(7):1598-608. DOI:10.1158/1535-7163.MCT-12-0102 · 5.68 Impact Factor
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    ABSTRACT: Emerging evidence suggests that feeding a high-fat diet (HFD) to rodents affects the expression of genes involved in drug transport. However, gender-specific effects of HFD on drug transport are not known. The multidrug resistance-associated protein 2 (Mrp2, Abcc2) is a transporter highly expressed in the hepatocyte canalicular membrane and is important for biliary excretion of glutathione-conjugated chemicals. The current study showed that hepatic Mrp2 expression was reduced by HFD feeding only in female, but not male, C57BL/6J mice. In order to determine whether down-regulation of Mrp2 in female mice altered chemical disposition and toxicity, the biliary excretion and hepatotoxicity of the Mrp2 substrate, α-naphthylisothiocyanate (ANIT), were assessed in male and female mice fed control diet or HFD for 4weeks. ANIT-induced biliary injury is a commonly used model of experimental cholestasis and has been shown to be dependent upon Mrp2-mediated efflux of an ANIT glutathione conjugate that selectively injures biliary epithelial cells. Interestingly, HFD feeding significantly reduced early-phase biliary ANIT excretion in female mice and largely protected against ANIT-induced liver injury. In summary, the current study showed that, at least in mice, HFD feeding can differentially regulate Mrp2 expression and function and depending upon the chemical exposure may enhance or reduce susceptibility to toxicity. Taken together, these data provide a novel interaction between diet and gender in regulating hepatobiliary excretion and susceptibility to injury.
    Toxicology and Applied Pharmacology 04/2012; 261(2):189-95. DOI:10.1016/j.taap.2012.04.001 · 3.71 Impact Factor
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    ABSTRACT: Excessive signaling from the Wnt pathway is associated with numerous human cancers. Using a high throughput screen designed to detect inhibitors of Wnt/β-catenin signaling, we identified a series of acyl hydrazones that act downstream of the β-catenin destruction complex to inhibit both Wnt-induced and cancer-associated constitutive Wnt signaling via destabilization of β-catenin. We found that these acyl hydrazones bind iron in vitro and in intact cells and that chelating activity is required to abrogate Wnt signaling and block the growth of colorectal cancer cell lines with constitutive Wnt signaling. In addition, we found that multiple iron chelators, desferrioxamine, deferasirox, and ciclopirox olamine similarly blocked Wnt signaling and cell growth. Moreover, in patients with AML administered ciclopirox olamine, we observed decreased expression of the Wnt target gene AXIN2 in leukemic cells. The novel class of acyl hydrazones would thus be prime candidates for further development as chemotherapeutic agents. Taken together, our results reveal a critical requirement for iron in Wnt signaling and they show that iron chelation serves as an effective mechanism to inhibit Wnt signaling in humans.
    Cancer Research 12/2011; 71(24):7628-39. DOI:10.1158/0008-5472.CAN-11-2745 · 9.33 Impact Factor
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    ABSTRACT: Advancing novel therapeutic agents for the treatment of malignancy into the marketplace is an increasingly costly and lengthy process. As such, new strategies for drug discovery are needed. Drug repurposing represents an opportunity to rapidly advance new therapeutic strategies into clinical trials at a relatively low cost. Known on-patent or off-patent drugs with unrecognized anticancer activity can be rapidly advanced into clinical testing for this new indication by leveraging their known pharmacology, pharmacokinetics, and toxicology. Using this approach, academic groups can participate in the drug discovery field and smaller biotechnology companies can "de-risk" early-stage drug discovery projects. Here, several scientific approaches used to identify drug repurposing opportunities are highlighted, with a focus on hematologic malignancies. In addition, a discussion of the regulatory issues that are unique to drug repurposing and how they impact developing old drugs for new indications is included. Finally, the mechanisms to enhance drug repurposing through increased collaborations between academia, industry, and nonprofit charitable organizations are discussed.
    Blood 06/2011; 117(25):6747-55. DOI:10.1182/blood-2011-02-315283 · 10.45 Impact Factor
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    ABSTRACT: 6-Cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone (ciclopirox) and specifically its olamine salt 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone 2-aminoethanol salt (ciclopirox olamine) are anti-fungal agents currently used for the treatment of mild to moderate cutaneous fungal infection. Our objective is to comment on the opportunity to rapidly reposition ciclopirox and its olamine for the treatment of haematologic malignancy by leveraging its prior published toxicology and pharmacology data. Ciclopirox olamine chelates intracellular iron and displays preclinical efficacy in the treatment of haematologic malignancy. Currently, an ongoing study is evaluating topical ciclopirox olamine for the treatment of cervical cancer. Doses of ciclopirox olaine required for a systemic anti-cancer effect appear pharmacologically achievable. However, caution is required as at the highest doses tested in animal toxicology studies, irreversible cardiac degeneration was observed. The existing pharmacology and toxicology data suggest that systemic ciclopirox olamine could be repositioned as a new investigational anti-cancer agent. The available pharmacology and toxicology data should aid in the design of phase I clinical trials of this agent in patients with refractory haematologic malignancies.
    Journal of Clinical Pharmacy and Therapeutics 04/2011; 36(2):128-34. DOI:10.1111/j.1365-2710.2010.01172.x · 1.67 Impact Factor
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    ABSTRACT: A series of N-acyl O-amino derivatives of seco-CBI-indole(2) are reported and examined as prototypical members of a unique class of reductively activated (cleaved) prodrugs of the duocarmycin and CC-1065 family of antitumor agents. These prodrugs were designed to be potentially preferentially activated in hypoxic tumor environments which carry an intrinsically higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives by nucleophilic cleavage of a weak N-O bond. A remarkable range of stabilities and a resulting direct correlation with in vitro/in vivo biological potencies was observed for these prodrugs, even enlisting subtle variations in the electronic and steric environment around the weak N-O bond. An in vivo evaluation of several of the prodrugs demonstrates that some approach the potency and exceed the efficacy of the free drug itself (CBI-indole(2)), suggesting the prodrugs may offer an additional advantage related to a controlled or targeted release.
    Journal of Medicinal Chemistry 10/2010; 53(21):7731-8. DOI:10.1021/jm1010397 · 5.45 Impact Factor
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    ABSTRACT: The objective of this study was to optimize the in vivo activity of proteolipid protein (PLP)-bifunctional peptide inhibitor (BPI) molecule to suppress experimental autoimmune encephalomyelitis (EAE) in SJL/J mice and evaluate pharmacokinetic profiles of PLP-BPI. PLP-BPI is constructed via conjugation of myelin PLP(139-151) with CD11a(237-246)-derived peptide (LABL) via a spacer. The hypothesis is that PLP-BPI binds simultaneously to major histocompatibility complex-II and intercellular adhesion molecule-1 on the antigen-presenting cell (APC) and inhibits the formation of the immunological synapse during T-cell and APC interactions. In this study, the structure of BPI was modified by varying the spacer and was evaluated in the EAE model. Intravenous injections of BPI derivatives inhibited the onset, severity, and incidence of EAE more effectively and induced a lower incidence of anaphylaxis than that produced by unmodified PLP-BPI. As anticipated, production of interleukin-17, a proinflammatory cytokine commonly found in elevated levels among multiple sclerosis (MS) patients, was significantly lower in Ac-PLP-BPI-PEG6- or Ac-PLP-BPI-NH(2)-2-treated mice than in phosphate-buffered saline-treated mice. These results suggest that BPI-type molecules can be modified to achieve more efficient and better tolerated BPI-based derivatives for the treatment of MS.
    Journal of Pharmacology and Experimental Therapeutics 12/2009; 332(3):1136-45. DOI:10.1124/jpet.109.161109 · 3.97 Impact Factor
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    ABSTRACT: Academic research has contributed immensely in advancing the frontiers of science related to therapeutic areas. However, it has generally been the biotechnology and the pharmaceutical industries that contributed to the discovery and development of new drugs. The primary reason for this disparity has been the cost of the various facets of modern drug discovery. In recent years, high throughput screening (HTS) has been a major component in advancing new lead discovery research in Pharma. Academia and the smaller biotech firms simply could not participate in HTS efforts because of the high capital investment needed in setting up HTS laboratories. Similarly, Pharma neglected to address disease targets that are either financially too risky or scientifically impractical to implement. To bridge the gap in this disparity, academia is setting up HTS laboratories with funding from the appropriate government agencies to address the unmet critical needs by creating a new paradigm for drug discovery that integrates the best of big Pharma, Biotech and Academia. This has also become possible due to a change in the mindset of the academic researchers who long held the view that HTS is an anti-intellectual endeavour, but have since come to appreciate the strength of HTS in new lead discovery and in the development of molecular probes. The challenge that remains to be addressed by academia is the end goal of HTS. Is the goal just to find a 'tool' molecule or is it to discover and develop a 'drug'? What processes and collaborations have been set in place to transform a hit to a lead? With 'publish or perish' dogma that is prevalent in academia, protection of intellectual property rights is a formidable task even if one finds the proverbial 'needle in a haystack'. High throughput screening is a great concept and holds promise for academia, but to follow the pharmaceutical paradigm in transforming a screen hit to a lead, and eventually into a drug is easier said than done. The reality: academia is ready for it. The drug discovery and development initiatives at the University of Kansas (KU) are a prime example.
    Drug Discovery World 09/2008; Fall:59-74.
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    ABSTRACT: N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1-0.01% free drug release) and pH 7.0 phosphate buffer, and exhibit a robust half-life in human plasma (t1/2 = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo.
    Journal of the American Chemical Society 12/2007; 129(49):15391-7. DOI:10.1021/ja075398e · 12.11 Impact Factor

Publication Stats

151 Citations
123.32 Total Impact Points


  • 2010–2014
    • University of Kansas
      • • Department of Pharmacology and Toxicology
      • • Institute for Advancing Medical Innovation
      Lawrence, Kansas, United States
  • 2011–2012
    • Kansas City VA Medical Center
      Kansas City, Missouri, United States
  • 2007
    • The Scripps Research Institute
      • Skaggs Institute for Chemical Biology
      La Jolla, CA, United States