RhoB in cancer pathogenesis and as a target in combinatorial therapy

Summary

Principal Investigator: ROBERT SMALLRIDGE
Abstract: DESCRIPTION (Provided By Applicant): In examining the potent novel high affinity PPAR3 agonist, RS5444, as a candidate cancer therapeutic, we discovered that RhoB mRNA and protein were rapidly upregulated by RS5444 in concert with observed antineoplastic effects. This prompted us to examine the novel hypothesis that downstream RhoB effects in part mediate the contributions of PPAR3 to cancer pathogenesis. RhoB is a small GTPase regulating actin organization and vesicle transport not mutated in cancer. RhoB, however, inhibits proliferation. We had previously showed RS5444 and paclitaxel can be combined synergistically in anaplastic thyroid cancer (ATC) models in vitro and in vivo and that the cyclin kinase inhibitor, p21WAF1/CIP1 (p21), is necessary for PPAR3- mediated growth inhibition and for the apoptotic synergy induced by the combination. We now report that RhoB is critical for RS5444/PPAR3-mediated p21 mRNA and protein induction. Silencing RhoB in our laboratory resulted in loss of growth inhibitory activity by RS5444, bolstering our hypothesis, and leading us to demonstrate for the first time that forced RhoB upregulation leads to cancer cell death in ATC. These data, coupled with preliminary data of RhoB down-regulation in our archival ATC tissues, led us to hypothesize that RhoB is important in the chemosensitivity of ATC and in ATC pathogenesis. Based upon these findings, a Phase 1/2 clinical trial combining RS5444 and paclitaxel is under way in ATC in efforts to improve the single agent effects of paclitaxel 3 in this nearly uniformly fatal cancer. Tumor biopsies obtained in conjunction with this trial will allow measurement of RhoB and p21 induction as early response correlates to patient outcome. RS5444 alone induces G0/G1 cell cycle arrest without apoptosis in ATC and forced expression of RhoB (Tet RhoB) proves sufficient for induction of p21, G2/M arrest and apoptosis. These observations coupled with another discovery that RhoB mislocalizes to the nucleus, colocalizing with p21 in a nuclear complex that includes protein kinase C-related kinase one (PRK1), a known RhoB interacting protein and serine/threonine kinase. This complex forms as a result of RS5444 as well as forced RhoB expression leading us to hypothesize that this novel nuclear complex mediates RhoB antitumor activity via direct interaction with cell cycle machinery complexes and that post-translational modifications of p21 direct its physical association with either G0/G1 or G2/M cell cycle machinery thereby specifying cell cycle arrest or apoptosis. In Aim 1, we will elaborate the mechanism(s) by which RhoB mediates cell cycle arrest and apoptosis via this novel nuclear complex. In Aim 2, the role of RhoB in apoptotic and antitumor synergy will be defined in animal models as well as using other newly discovered drugs upregulating RhoB that may be useful for patients with PPAR3- negative ATC. In Aim 3, we will develop prognostic indicators for response to therapy. Our data indicate RhoB as a novel molecular switch dictating cell fate. Thusly, proposed studies have potential not only to improve understanding of RhoB signaling, but to ultimately lead to improved therapeutic approaches in ATC.
Funding Period: 2010-07-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc Detailed molecular fingerprinting of four new anaplastic thyroid carcinoma cell lines and their use for verification of RhoB as a molecular therapeutic target
    Laura A Marlow
    Mayo Clinic, Department of Cancer Biology, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
    J Clin Endocrinol Metab 95:5338-47. 2010
  2. ncbi The combination of an mTORc1/TORc2 inhibitor with lapatinib is synergistic in bladder cancer in vitro
    Marie N Becker
    Division of Urology, Department of Surgery, College of Medicine Jacksonville, University of Florida, Jacksonville, FL Electronic address
    Urol Oncol 32:317-26. 2014
  3. pmc Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma
    Christina A von Roemeling
    Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224, USA
    Clin Cancer Res 19:2368-80. 2013
  4. pmc Efatutazone, an oral PPAR-γ agonist, in combination with paclitaxel in anaplastic thyroid cancer: results of a multicenter phase 1 trial
    R C Smallridge
    Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
    J Clin Endocrinol Metab 98:2392-400. 2013
  5. pmc Pazopanib enhances paclitaxel-induced mitotic catastrophe in anaplastic thyroid cancer
    Crescent R Isham
    Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
    Sci Transl Med 5:166ra3. 2013
  6. pmc PRSS3/mesotrypsin is a therapeutic target for metastatic prostate cancer
    Alexandra Hockla
    Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
    Mol Cancer Res 10:1555-66. 2012
  7. pmc Approach to the patient with anaplastic thyroid carcinoma
    Robert C Smallridge
    Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
    J Clin Endocrinol Metab 97:2566-72. 2012
  8. pmc Foxo3a drives proliferation in anaplastic thyroid carcinoma through transcriptional regulation of cyclin A1: a paradigm shift that impacts current therapeutic strategies
    Laura A Marlow
    Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224, USA
    J Cell Sci 125:4253-63. 2012
  9. pmc RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer
    Prakash Vishnu
    Department of Hematology Oncology, Mayo Clinic, Jacksonville, FL 32224, USA
    Gynecol Oncol 124:589-97. 2012
  10. pmc RNA sequencing identifies multiple fusion transcripts, differentially expressed genes, and reduced expression of immune function genes in BRAF (V600E) mutant vs BRAF wild-type papillary thyroid carcinoma
    Robert C Smallridge
    Department of Medicine R C S, Division of Endocrinology and Metabolism, Mayo Clinic, Jacksonville, Florida 32224 Department of Otorhinolaryngology Head and Neck Surgery A M C, J D C, Mayo Clinic, Jacksonville, Florida 32224 Department of Health Sciences Research Y W A, D J S, Mayo Clinic, Jacksonville, Florida 32224 Department of Medicine, Division of Endocrinology H V R, N L E, B M, Mayo Clinic, Rochester, Minnesota 55905 Department of Laboratory Medicine and Pathology K W C, S K G, Division of Clinical Biochemistry and Immunology, Mayo Clinic, Rochester, Minnesota 55905 Department of Laboratory Medicine and Pathology M R, Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota 55905 Department of Cancer Biology B N, J M C, J A C, E A T, Mayo Clinic, Jacksonville, Florida 32224 and Department of Biochemistry and Molecular Biology N L E, Mayo Clinic, Rochester, Minnesota 55905
    J Clin Endocrinol Metab 99:E338-47. 2014

Research Grants

  1. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
  2. Chicago Prevention and Intervention Epicenter (Chicago PIE)
    ROBERT ALAN WEINSTEIN; Fiscal Year: 2013
  3. Spatial and Temporal Regulation of Angiogenesis
    HAROLD FISHER DVORAK; Fiscal Year: 2013

Detail Information

Publications10

  1. pmc Detailed molecular fingerprinting of four new anaplastic thyroid carcinoma cell lines and their use for verification of RhoB as a molecular therapeutic target
    Laura A Marlow
    Mayo Clinic, Department of Cancer Biology, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
    J Clin Endocrinol Metab 95:5338-47. 2010
    ..Up to 42% of human thyroid cancer cell lines are redundant or not of correct tissue origin, and a comprehensive analysis is currently nonexistent. Mechanistically, RhoB has been identified as a novel molecular target for ATC therapy...
  2. ncbi The combination of an mTORc1/TORc2 inhibitor with lapatinib is synergistic in bladder cancer in vitro
    Marie N Becker
    Division of Urology, Department of Surgery, College of Medicine Jacksonville, University of Florida, Jacksonville, FL Electronic address
    Urol Oncol 32:317-26. 2014
    ..To examine the ability of dual mTORc1/c2 inhibitors in conjunction with lapatinib to function in a synergistic manner to inhibit cell proliferation and anchorage-independent growth in bladder cancer cell lines...
  3. pmc Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma
    Christina A von Roemeling
    Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224, USA
    Clin Cancer Res 19:2368-80. 2013
    ..S. Food and Drug Administration (FDA)-approved regimens...
  4. pmc Efatutazone, an oral PPAR-γ agonist, in combination with paclitaxel in anaplastic thyroid cancer: results of a multicenter phase 1 trial
    R C Smallridge
    Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
    J Clin Endocrinol Metab 98:2392-400. 2013
    ..A phase 1 study was initiated to determine the safety, potential effectiveness, and maximal tolerated dose and recommended phase 2 dose of efatutazone and paclitaxel in anaplastic thyroid cancer...
  5. pmc Pazopanib enhances paclitaxel-induced mitotic catastrophe in anaplastic thyroid cancer
    Crescent R Isham
    Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
    Sci Transl Med 5:166ra3. 2013
    ..Collectively, these results suggest that the pazopanib/paclitaxel combination is a promising candidate therapeutic approach in ATC and that aurora A may represent a potentially viable therapeutic molecular target in ATC...
  6. pmc PRSS3/mesotrypsin is a therapeutic target for metastatic prostate cancer
    Alexandra Hockla
    Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
    Mol Cancer Res 10:1555-66. 2012
    ..This study defines mesotrypsin as an important mediator of prostate cancer progression and metastasis, and suggests that inhibition of mesotrypsin activity may provide a novel modality for prostate cancer treatment...
  7. pmc Approach to the patient with anaplastic thyroid carcinoma
    Robert C Smallridge
    Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
    J Clin Endocrinol Metab 97:2566-72. 2012
    ..Prospective multicenter clinical trials, incorporating molecular analyses of tumors, are required if we are to improve survival in anaplastic thyroid carcinoma...
  8. pmc Foxo3a drives proliferation in anaplastic thyroid carcinoma through transcriptional regulation of cyclin A1: a paradigm shift that impacts current therapeutic strategies
    Laura A Marlow
    Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224, USA
    J Cell Sci 125:4253-63. 2012
    ..This new paradigm also suggests caution in relation to current dogma focused upon reactivation of FoxO3a as a therapeutic strategy against cancers harboring active PI3-K and Akt signaling pathways...
  9. pmc RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer
    Prakash Vishnu
    Department of Hematology Oncology, Mayo Clinic, Jacksonville, FL 32224, USA
    Gynecol Oncol 124:589-97. 2012
    ....
  10. pmc RNA sequencing identifies multiple fusion transcripts, differentially expressed genes, and reduced expression of immune function genes in BRAF (V600E) mutant vs BRAF wild-type papillary thyroid carcinoma
    Robert C Smallridge
    Department of Medicine R C S, Division of Endocrinology and Metabolism, Mayo Clinic, Jacksonville, Florida 32224 Department of Otorhinolaryngology Head and Neck Surgery A M C, J D C, Mayo Clinic, Jacksonville, Florida 32224 Department of Health Sciences Research Y W A, D J S, Mayo Clinic, Jacksonville, Florida 32224 Department of Medicine, Division of Endocrinology H V R, N L E, B M, Mayo Clinic, Rochester, Minnesota 55905 Department of Laboratory Medicine and Pathology K W C, S K G, Division of Clinical Biochemistry and Immunology, Mayo Clinic, Rochester, Minnesota 55905 Department of Laboratory Medicine and Pathology M R, Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota 55905 Department of Cancer Biology B N, J M C, J A C, E A T, Mayo Clinic, Jacksonville, Florida 32224 and Department of Biochemistry and Molecular Biology N L E, Mayo Clinic, Rochester, Minnesota 55905
    J Clin Endocrinol Metab 99:E338-47. 2014
    ..The BRAF V600E mutation (BRAF-MUT) confers an aggressive phenotype in papillary thyroid carcinoma, but unidentified additional genomic abnormalities may be required for full phenotypic expression...

Research Grants30

  1. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  2. Chicago Prevention and Intervention Epicenter (Chicago PIE)
    ROBERT ALAN WEINSTEIN; Fiscal Year: 2013
    ..The impact on ICU infection and prescribing characteristics of doctors will be assessed. To further assess the interventions, costs of averted outcomes and of the interventions will be compared. OPRIONAL OBEJCTIVE SCORE: 2 ..
  3. Spatial and Temporal Regulation of Angiogenesis
    HAROLD FISHER DVORAK; Fiscal Year: 2013
    ..abstract_text> ..