OKLAHOMA CITY, OK, United States
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Sureban S.M.,The University of Oklahoma Health Sciences Center | Sureban S.M.,The Peggy and Charles Stephenson Cancer Center | May R.,The University of Oklahoma Health Sciences Center | Weygant N.,The University of Oklahoma Health Sciences Center | And 10 more authors.
Cancer Letters | Year: 2014

XMD8-92 is a kinase inhibitor with anti-cancer activity against lung and cervical cancers, but its effect on pancreatic ductal adenocarcinoma (PDAC) remains unknown. Doublecortin-like kinase1 (DCLK1) is upregulated in various cancers including PDAC. In this study, we showed that XMD8-92 inhibits AsPC-1 cancer cell proliferation and tumor xenograft growth. XMD8-92 treated tumors demonstrated significant downregulation of DCLK1 and several of its downstream targets (including c-MYC, KRAS, NOTCH1, ZEB1, ZEB2, SNAIL, SLUG, OCT4, SOX2, NANOG, KLF4, LIN28, VEGFR1, and VEGFR2) via upregulation of tumor suppressor miRNAs let-7a, miR-144, miR-200a-c, and miR-143/145; it did not however affect BMK1 downstream genes p21 and p53. These data taken together suggest that XMD8-92 treatment results in inhibition of DCLK1 and downstream oncogenic pathways (EMT, pluripotency, angiogenesis and anti-apoptotic), and is a promising chemotherapeutic agent against PDAC. © 2014.


Weygant N.,The University of Oklahoma Health Sciences Center | Qu D.,The University of Oklahoma Health Sciences Center | Qu D.,Peggy and Charles Stephenson Oklahoma Cancer Center | May R.,The University of Oklahoma Health Sciences Center | And 15 more authors.
Oncotarget | Year: 2015

Renal clear cell carcinoma (RCC) is the most common type of kidney cancer and the 8th most common cancer overall in the US. RCC survival rates drop precipitously with regional and distant spread and recent studies have demonstrated that RCC presents an epithelial-mesenchymal transition (EMT) phenotype linked to increased recurrence and decreased survival. EMT is a key characteristic of tumor stem cells (TSCs) along with chemo-resistance and radio-resistance, which are also phenotypic of RCC. Targeting these factors is key to increasing the survival of RCC patients. Doublecortin-like kinase 1 (DCLK1) marks TSCs in pancreatic and colorectal cancer and regulates EMT and stemness. Analysis of the Cancer Genome Atlas' RCC dataset revealed that DCLK1 is overexpressed and dysregulated on the mRNA and epigenetic level in more than 93% of RCC tumors relative to adjacent normal tissue. Immunohistochemistry using α-DCLK1 antibody confirmed overexpression and demonstrated a major increase in immunoreactivity in stage II-III tumors compared to normal kidney and stage I tumors. Small-interfering RNA (siRNA) mediated knockdown of DCLK1 resulted in decreased expression of EMT and pluripotency factors and significantly reduced invasion, migration, focal adhesion, drug-resistance, and clonogenic capacity. These findings suggest that DCLK1 is a novel, overexpressed factor in RCC progression that may be targeted to suppress EMT, metastasis, and stemness in early-stage and advanced RCC to increase patient survival. Moreover, the possibility that DCLK1 may mark a population of tumor stem-like cells in RCC should be further investigated in light of these findings.


Weygant N.,The University of Oklahoma Health Sciences Center | Qu D.,The University of Oklahoma Health Sciences Center | Berry W.L.,Peggy and Charles Stephenson Oklahoma Cancer Center | Berry W.L.,The University of Oklahoma Health Sciences Center | And 11 more authors.
Molecular Cancer | Year: 2014

Background: Doublecortin-like kinase 1 (DCLK1) is emerging as a tumor specific stem cell marker in colorectal and pancreatic cancer. Previous in vitro and in vivo studies have demonstrated the therapeutic effects of inhibiting DCLK1 with small interfering RNA (siRNA) as well as genetically targeting the DCLK1+ cell for deletion. However, the effects of inhibiting DCLK1 kinase activity have not been studied directly. Therefore, we assessed the effects of inhibiting DCLK1 kinase activity using the novel small molecule kinase inhibitor, LRRK2-IN-1, which demonstrates significant affinity for DCLK1.Results: Here we report that LRRK2-IN-1 demonstrates potent anti-cancer activity including inhibition of cancer cell proliferation, migration, and invasion as well as induction of apoptosis and cell cycle arrest. Additionally we found that it regulates stemness, epithelial-mesenchymal transition, and oncogenic targets on the molecular level. Moreover, we show that LRRK2-IN-1 suppresses DCLK1 kinase activity and downstream DCLK1 effector c-MYC, and demonstrate that DCLK1 kinase activity is a significant factor in resistance to LRRK2-IN-1.Conclusions: Given DCLK1's tumor stem cell marker status, a strong understanding of its biological role and interactions in gastrointestinal tumors may lead to discoveries that improve patient outcomes. The results of this study suggest that small molecule inhibitors of DCLK1 kinase should be further investigated as they may hold promise as anti-tumor stem cell drugs. © 2014 Weygant et al.; licensee BioMed Central Ltd.


Sureban S.M.,The University of Oklahoma Health Sciences Center | Sureban S.M.,Peggy and Charles Stephenson Cancer Center | May R.,The University of Oklahoma Health Sciences Center | Qu D.,The University of Oklahoma Health Sciences Center | And 11 more authors.
PLoS ONE | Year: 2013

Stem cell pluripotency, angiogenesis and epithelial-mesenchymal transition (EMT) have been shown to be significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) and many other aggressive cancers. The dysregulation of these processes is believed to play key roles in tumor initiation, progression, and metastasis, and is contributory to PDAC being the fourth leading cause of cancer-related deaths in the US. The tumor suppressor miRNA miR-145 downregulates critical pluripotency factors and oncogenes and results in repressed metastatic potential in PDAC. Additionally, the miR-200 family regulates several angiogenic factors which have been linked to metastasis in many solid tumors. We have previously demonstrated that downregulation of DCLK1 can upregulate critical miRNAs in both in vitro and in vivo cancer models and results in downregulation of c-MYC, KRAS, NOTCH1 and EMT-related transcription factors. A recent report has also shown that Dclk1 can distinguish between normal and tumor stem cells in Apcmin/+ mice and that ablation of Dclk1+ cells resulted in regression of intestinal polyps without affecting homeostasis. Here we demonstrate that the knockdown of DCLK1 using poly(lactide-co-glycolide)-encapsulated-DCLK1-siRNA results in AsPC1 tumor growth arrest. Examination of xenograft tumors revealed, (a) increased miR-145 which results in decreased pluripotency maintenance factors OCT4, SOX2, NANOG, KLF4 as well as KRAS and RREB1; (b) increased let-7a which results in decreased pluripotency factor LIN28B; and (c) increased miR-200 which results in decreased VEGFR1, VEGFR2 and EMT-related transcription factors ZEB1, ZEB2, SNAIL and SLUG. Specificity of DCLK1 post-transcriptional regulation of the downstream targets of miR-145, miR-200 and let-7a was accomplished utilizing a luciferase-based reporter assay. We conclude that DCLK1 plays a significant master regulatory role in pancreatic tumorigenesis through the regulation of multiple tumor suppressor miRNAs and their downstream pro-tumorigenic pathways. This novel concept of targeting DCLK1 alone has several advantages over targeting single pathway or miRNA-based therapies for PDAC. © 2013 Sureban et al.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 905.99K | Year: 2016

Abstract Pancreatic ductal adenocarcinoma PDAC is a devastating cancer with an extremely low year survival rate even for those who are diagnosed early Novel research suggests that this may be the result of metastatic dissemination preceding or concurrent to the development of the primary tumor Epithelial mesenchymal transition EMT is one of the key pathways in pancreatic cancer invasion and metastasis and is linked to a tumor stem cell phenotype The COARE Biotechnology Randamp D team believes that targeting this process will ultimately allow us to significantly increase patient survival COAREandapos s primary expertise is in targeting cancer through the doublecortin like kinase DCLK tumor stem cell marker During COAREandapos s Phase I SBIR study of a mouse monoclonal antibody mAb raised against DCLK CBT that showed promising results in vitro and in vivo COARE Biotechnology engineered a newer generation of mAb designed to take advantage of DCLK andapos s cell surface antigen expressed on pancreatic cancer tumors circulating tumor cells and metastases which led to a powerful anti tumorigenic effect in PDAC tumor xenografts For this Phase II project we propose to further develop this mAb termed raphtumomab in preparation for commercialization and human clinical trials We will pursue this objective with the following three specific aims Aim COARE in collaboration with Panorama Research Institute will humanize raphtumomab to create raphtuzumab and will confirm retained binding affinity for DCLK by BIAcore and other techniques Aim COARE in collaboration with the University of Oklahoma Health Sciences Center will assess raphtuzumab to determine its pharmacokinetic dynamic PK PD properties mechanism of action MOA and its continued preclinical efficacy in patient derived orthotopic models of PDAC Aim COARE in collaboration with WIL Research will perform IND enabling toxicity and immunogenicity studies of raphtuzumab in Sprague Dawley rats SDR and non human primates NHPs Milestones Raphtuzumab will demonstrate retained DCLK affinity nM a DCLK MOA andgt reduction in EMT and DCLK expression continued preclinical efficacy including a andgt fold reduction in patient derived orthotopic model tumorigenesis suitable PK PD toxicity and immunogenicity in SDR and NHPs Desired Outcome Phase II SBIR success provide the key results and data needed to engage private sector investors partners in carrying out the next steps toward the regulatory approval required to begin clinical trials in PDAC patients Success with the clinical trials will lead to ultimate commercialization When raphtuzumab reaches the market COARE Biotechnology envisions that it will be the first treatment for PDAC that can significantly increase patient overall survival Project Narrative Pancreatic ductal adenocarcinoma PDAC is one of the deadliest cancers with dismal survival even in patients with early stage disease Based on successful Phase I SBIR feasibility studies of a novel monoclonal antibody CBT targeting the DCLK tumor stem cell marker protein in PDAC COARE Biotechnology has developed a next generation therapeutic monoclonal antibody raphtumomab with the potential to improve PDAC patient outcomes by decreasing the tumor stem cell supported epithelial mesenchymal transition process that fuels metastasis For the follow on Phase II SBIR study proposed here COARE will team with several expert collaborators to humanize this promising antibody drug and will perform IND enabling studies to prepare for clinical trials and ultimate commercialization of a next generation therapeutic that has the potential to greatly impact positive human health outcomes for PDAC patients


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2015

DESCRIPTION provided by applicant Pancreatic ductal adenocarcinoma PDAC is one of the most devastating human cancers It is the fourth leading cause of cancer related deaths in the U S with a year survival rate Despite FDA approved therapeutic regimens and advances in medical and surgical care no significant impact on PDAC patient survival has been observed In an estimated Americans were expected to be diagnosed and were expected to die from PDAC There is increasing evidence that most solid tumors including PDAC have a sub population of tumor initiating cells termed tumor stem cells TSCs and that epithelial mesenchymal transition EMT a key feature in cancer invasion and metastasis is linked to a TSC phenotype COARE has shown that the TSC marker DCLK is significantly upregulated in PDAC and is a central regulator of pluripotency and EMT DCLK is overexpressed in PDAC epithelia and stroma where it strongly correlates to pancreatic intraepithelial lesion stage and inhibition of DCLK by siRNA triggers a signaling cascade that reduces stemness and EMT in PDAC cells Recent studies definitively confirmed Dclk andapos s TSC status in the Apcmin model of intestinal neoplasia and a similar role for Dclk in PDAC initiation is indicated by lineage tracing mouse models Recent studies also indicate that Dclk marks a population of cancer initiating cells with TSC characteristics that fuel pre invasive invasive cancer in multiple mouse models of PDAC To date experiments targeting DCLK in colorectal cancer and PDAC xenograft models have demonstrated inhibition of EMT and pluripotency factors leading to reduced invasion and tumor growth arrest DCLK is a unique TSC marker that contains an extracellular C terminal domain expressed in the primary tumor and circulating tumor cells CTCs Antibody drug conjugates ADCs allow the specific targeting of tumor cell surface expressed antigens with cytotoxins with the potential benefits of enhanced efficacy and reduced off target toxicity Recently Abraxane r a formulation based on Paclitaxel PTX was FDA approved for PDAC treatment in combination with gemcitabine COAREandapos s CBT is a PTX based ADC targeting the DCLK TSC CTC antigen in PDAC with potential to improve outcomes in locally advanced metastatic PDAC Two Specific Aims will be pursued demonstrate that CBT effectively delivers a cytotoxic payload to PDAC cells and demonstrate that CBT suppresses tumor growth in orthotopic PDAC models with or without gemcitabine and prevents in vivo metastasis Test of Feasibility CBT should induce cell death and inhibit proliferation comparable to PTX alone It should also significantly inhibit cell invasiveness and demonstrate internalization of PTX In in vivo models CBT should clearly reduce tumor growth and metastasis and result in decreased DCLK expression due to DCLK cell death precipitating reduced expression of stemness and EMT factors regulated by DCLK compared to controls Phase I success will lead to a follow on Phase II validation project and ultimately Phase III commercialization PUBLIC HEALTH RELEVANCE Pancreatic cancer is the Nationandapos s fourth leading cause of cancer related death and has a dismal year survival rate of only a The COARE Biotechnology Randamp D team has identified a new antibody drug conjugate based approach that shows significant promise in eliminating the current barriers to successful treatment of locally advanced and or metastatic pancreatic cancer This SBIR project is focused on proving the feasibility of pursuing this approach as a therapy for improving outcomes in advanced and metastatic pancreatic cancer


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.95K | Year: 2015

DESCRIPTION provided by applicant Colorectal cancer CRC is the third leading cause of cancer related death in the U S Although advances in CRC screening surgical therapies and medical management have improved clinical outcomes there still is a major need to develop better medical therapies for CRC particularly among those with advanced local or metastatic disease The year survival rate of victims with stage IV disease is a dismal There is increasing evidence that most solid tumors including CRC have a subpopulation of tumor initiating cells termed tumor stem cells TSCs Epithelial mesenchymal transition EMT is a key feature in cancer invasion and metastasis and is linked to a TSC phenotype in CRC The COARE team has demonstrated that the tumor stem cell marker DCLK is significantly upregulated in CRC and is a central regulator of key oncogenic pathways and EMT Recent studies have definitively confirmed DCLK andapos s TSC status in the Apcmin model of intestinal neoplasia COAREandapos s pre clinical experimental data shows that therapeutic targeting of cells that overexpress DCLK arrests tumor growth in xenografts and reduces the size and number of adenomas in Apcmin mice DCLK signaling inhibition triggers the induction activation of several critical endogenous tumor suppressor pathways within the tumor which in turn regulate oncogenic pathways and processes and EMT related transcription factors DCLK is a unique TSC marker because it contains an extracellular C terminal domain Antibody drug conjugates ADCs allow the specific targeting of tumor cell surface expressed antigens with cytotoxins with the potential benefits of enhanced efficacy and reduced off target toxicity COAREandapos s CBT is a Paclitaxel based ADC targeting the DCLK TSC CTC antigen in CRC with the potential to improve outcomes in locally advanced metastatic CRC We will pursue three Specific Aims Aim Demonstrate that CBT will effectively deliver a cytotoxic payload to CRC cells resulting in cell death Aim Demonstrate that CBT will suppress tumor growth in TSC derived tumor isografts Aim Demonstrate that CBT will suppress tumor growth in xenograft models of CRC with and without fluorouracil and prevent in vivo metastasis Test of Feasibility CBT should induce cell death and inhibit proliferation comparable to Paclitaxel PTX alone Additionally it should significantly inhibit cell invasiveness and demonstrate internalization of PTX In TSC isografts CBT treatment should precipitate a significant reduction andgt in tumor growth and andgt induction of tumor suppressors and loss of downstream oncogenic signaling compared to controls In the tumor xenografts CBT should significantly reduce tumor volume alone sensitize tumors to fluorouracil FU and prevent engraftment of metastatic CRC cells in an in vivo metastasis assay Phase I success will lead to a Phase II project focused on humanizing DCLK mAb completing detailed pharmacokinetics and in vivo toxicity analyses and preparing for IND clinical trial work to set th stage for ultimate commercialization PUBLIC HEALTH RELEVANCE Colorectal cancer is the Nationandapos s third leading cause of cancer related death and stage IV disease has a dismal year survival rate of only a The COARE Randamp D team has identified a new antibody drug conjugate based approach that shows significant promise in eliminating the current barriers to successful treatment of locally advanced and or metastatic colorectal cancer This SBIR project is focused on proving the feasibility of pursuing this approach as a therapy for improving outcomes in advanced and metastatic colorectal cancer


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 220.10K | Year: 2013

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a solid tumor and is the fourth leading cause of cancer-related death in the U.S. The 5-year survival rate of its victims is lt5%. There is increasing evidence that most solidtumors have a subpopulation of tumor-initiating cells termed cancer stem cells (CSCs). The inability to eradicate these CSCs is postulated to be the reason for tumor relapse and death following initial responses to the current standard therapeutic regimen. In addition to the existence of CSCs, a critical problem in combating solid tumors is the heterogeneity of cell types within the tumor microenvironment. This heterogeneity is further complicated by epithelial-mesenchymal transition (EMT), a process thatplays a key role in cancer invasion and metastasis. Thus successful treatment of pancreatic cancer requires the development of therapeutics that can attack multiple pro-tumorigenic pathways simultaneously. The COARE team has demonstrated that the putativestem cell protein DCLK1 is a central regulator of key stem cell and oncogenic PDAC pathways and EMT. COARE's pre-clinical experimental data shows that therapeutic targeting of cells that overexpress DCLK1 arrests tumor growth in animal models. DCLK1 signaling inhibition triggers the induction/activation of several critical endogenous tumor-suppressor pathways within the tumor, which in turn regulate several downstream oncogenes and cancer growth regulatory pathways and processes and EMT-related transcription factors. DCLK1 is overexpressed in many solid tumors. COARE has generated anti-human-DCLK1 mAbs that inhibit DCLK1 function upon binding. Thus, in this Phase I SBIR project we propose to prove the feasibility of optimizing CBT-1111 that targets DCLK1 asa next-generation treatment for eradicating PDAC. We will pursue three Specific Aims. Aim 1: Prove that we can identify a safe and effective dose of CBT-1111. Aim 2: Assess via mAb modifications if we can effectively deliver CBT-1111 to the animals and cells. Aim 3: Demonstrate the effects of CBT-1111 on suppressing primary and metastatic tumor growth in xenograft models using human pancreatic cancer cells, and assess the effects on candidate gene expression in vivo. Test of Feasibility: CBT-1111 should knock down at least 50% of DCLK1 mRNA and protein and their downstream oncogenic signaling proteins in vitro and in vivo with minimal/no toxicity effects. CBT-1111 tagged with Cy7 should be tracked once injected in animals/cells using whole-body and cellularlive imaging. Additionally, we must observe a significant reduction (gt3 fold) in tumor size of the CBT-1111 treated tumors vs. controls. We must observe a reduction in metastatic tumor uptake in the lungs and liver following treatment with CBT1111. Finally, we must observe a 2-fold increase in candidate tumor suppressor microRNAs and a corresponding gt40% reduction in downstream targets at the protein and mRNA level in xenograft residual tumors following treatment with CBT-1111. Phase I success will leadto a follow-on Phase II validation project and ultimate Phase III commercialization. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma is the nation's fourth leading cause of cancer-related death, and it's very poor response to treatment results in a 5-year survival rate of only a few percent. The COARE RandD team has identified a new approach that shows significant promise in eliminating the current barriers to successful treatment of pancreatic cancer. The SBIRproject proposed here is focused on proving the feasibility of pursuing this novel approach as a means of developing the first effective biologic treatment for this devastating disease.


PubMed | Capital Medical University, The University of Oklahoma Health Sciences Center, City of Hope National Medical Center and Coare Biotechnology, Inc.
Type: Journal Article | Journal: Cancer research | Year: 2016

Doublecortin-like kinase 1 (DCLK1) is a gastrointestinal (GI) tuft cell kinase that has been investigated as a biomarker of cancer stem-like cells in colon and pancreatic cancers. However, its utility as a biomarker may be limited in principle by signal instability and dilution in heterogeneous tumors, where the proliferation of diverse tumor cell lineages obscures the direct measurement of DCLK1 activity. To address this issue, we explored the definition of a miRNA signature as a surrogate biomarker for DCLK1 in cancer stem-like cells. Utilizing RNA/miRNA-sequencing datasets from the Cancer Genome Atlas, we identified a surrogate 15-miRNA expression signature for DCLK1 activity across several GI cancers, including colon, pancreatic, and stomach cancers. Notably, Cox regression and Kaplan-Meier analysis demonstrated that this signature could predict the survival of patients with these cancers. Moreover, we identified patient subgroups that predicted the clinical utility of this DCLK1 surrogate biomarker. Our findings greatly strengthen the clinical significance for DCLK1 expression across GI cancers. Further, they provide an initial guidepost toward the development of improved prognostic biomarkers or companion biomarkers for DCLK1-targeted therapies to eradicate cancer stem-like cells in these malignancies. Cancer Res; 76(14); 4090-9. 2016 AACR.


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