Scientific Accomplishments

Molecular Carcinogenesis & Chemoprevention  (MCC) is one of The Ohio State University Comprehensive Cancer Center’s six highly interactive cancer Research Programs. The programs comprise more than 200 leading scientists from 13 different colleges within OSU and affiliated academic institutions.

With a focus on molecular carcinogenesis, bionutrition, translational chemoprevention and dietary prevention research, the MCC has successfully supported basic research and a significant translational component that involves human chemoprevention studies or cancer preventive dietary and nutritional studies. 

The program’s translational research component includes more than 2,000 participants at OSU involved in chemoprevention or nutrition studies under the direction of program members.

Other accomplishments include:

Programmatic Funding 2009

  • NCI 1R21 Grant, “Targeting Proapoptotic PKCdelta Signaling in Hepatocellular Carcinoma” – Ching-shih Chen, PhD
  • NCI 1R21 Grant, “Indole 3-Carbinol Derivatives with Enhanced Chemopreventive Activities” – Ching-shih Chen, PhD
  • Army, “Tumor-Selective Targeting of Androgen Receptor Expression by Small-Molecule Agents” – Ching-shih Chen, PhD
  • NHLBI 3R01 Grant, “Molecular Mechanisms of Apoptosis in Monocytes” – Andrea Doseff, PhD
  • NCI 1 R01 Grant, “(ARRA) Chemoprevention of Head & Neck Cancer Using Controlled Release Polymers” – Susan Mallery, DDS, PhD
  • NIGMS 3T32 Grant, “(ARRA) Chemistry/Biology Interface Training” – Dehua Pei, PhD
  • NCI 1R21 Grant, “(ARRA) Prevention of Lung Tumors by Agents Using Concurrent & Sequential Treatment – Michael Pereira, PhD
  • NCI 3R00 Grant, “(ARRA) Genome-Wide Analysis of Transcription Factor Function in Prostate Cancer – Qianben Wang, PhD
  • NCR 4R00 Grant, “Genome-Wide Analysis Factor Function in Pancreatic Cancer” – Qianben Wang, PhD
  • NCI 3R01 Grant, “(ARRA) Keratinocytes Responses to VEGF in Carcinogenesis” – Traci Wilgus, PhD
  • MPP Group, “Analysis of Aromatase Inhibition Using In Vitro Assays” – Robert Brueggemeier, PhD
  • Next Pharmaceuticals, “Chromium Histidine Vs. Chromium Picolinate for Blood Sugar Effects” – Robert DiSilvestro, PhD
  • Albion Laboratories, “Comparison of Two Selenium Complexes” – Robert DiSilvestro, PhD
  • American Cancer Society, “Mucoadhesive Patch Delivery of Fenretinide and Berry Anthocyanins for Oral Cancer Prevention” – Susan Mallery, DDS, PhD

Selected Findings & Developments

The MCC is developing a skin carcinogenesis program focusing on the fundamental mechanisms of UV, chemical or HPV-induced carcinogenesis and how the process may be modulated by factors such as gender and immune status. In addition, diet and nutritional studies (e.g. Vitamin D) are now underway with MCC pilot grants. 

Discoveries & Inventions

UV-induced Oxidant Stress, PG metabolism & Skin Carcinogenesis

Studies by MCC members demonstrated that chronic exposure to UV light, the primary cause of skin cancer, results in the induction of high levels of cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production in the skin which contributes to carcinogenesis.

Gender & Skin Carcinogenesis

PG metabolism regulates the inflammatory response to UV exposure, and inflammatory mediators contribute to oxidative stress, DNA damage and carcinogenesis. MCC members demonstrated that this relationship may be significantly impacted by gender and host anti-oxidant status (Cancer Research 2007; 67(7):3468-74).

The group’s studies showed that Skh-1 male mice develop UV-induced skin cancers earlier, more frequently, with more aggressive histology and with larger size than female mice. Male mice developed less inflammatory response compared with females, and males showed more coetaneous oxidative DNA damage and lower antioxidant levels than the females. The results show a gender bias in skin carcinogenesis and suggest that the gender difference in tumor development is more influenced by the extent of oxidative DNA damage and antioxidant capacities than by inflammatory response.

DNA Damage & Repair in Response to UV Irradiation

MCC member Altaf Wani, PhD, has examined mechanisms of DNA damage and repair in response to UV irradiation and other DNA damaging agents (Nucleic Acids Res 2005; 33(13):4023-4034; Cancer Res 2006; 66(17):8590-8597; Nucleic Acids Res 2007; 35(16):5338-50; Oncogene 2007; 26(29):4199-20). With more than 30 proteins involved in Nucleotide Excision Repair (NER), the major DNA repair process that removes diverse DNA lesions (including UV-induced photoproducts), XPC is thought to be one of the first proteins to recognize DNA damage during global genomic repair (GGR), a sub-pathway of NER. Dr. Wani’s group has shown that XPC is modified by SUMO-1 and ubiquitin following UV irradiation, and that these modifications require the functions of DDB2 and XPA as well as the ubiquitin-proteasome system. The results also suggest that at least one function of UV-induced XPC sumoylation is related to the stabilization of XPC protein.

AKT/PDK-1 Inhibitor

MCC member Ching-Shih Chen, PhD, and his team were the first to report that celecoxib’s ability to enhance apoptosis in prostate cancer cells is, in part, independent of COX-2 inhibition (J Natl Cancer Inst 94: 585, 2002; Cancer Res 2004; 64(12):4309-4318) and directly caused by AKT signaling blockage via PDK-1.

OSU HDAC-42: Targeting Histone Deacetylase 

MCC member Ching-Shih Chen, PhD, developed a novel phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, (S)-HDAC-42. Dr Chen showed that a potent (S)-HDAC-42 was more powerful than SAHA in suppressing the viability of all prostate cancer cell lines evaluated with submicromolar IC50 values. Additionally, (S)-HDAC-42 exhibited distinctly superior apoptogenic potency to SAHA and caused markedly greater decreases in phospho-Akt, Bcl-xL, and survivin.

(S)-HDAC-42 is a potent orally bioavailable HDAC-inhibitor and targets regulating multiple aspects of cancer cell survival, which might have clinical value in prostate cancer chemotherapy, warranting further investigation (Clin Cancer Res 2006; 12(17):5199-5206). 

Omega-3 Lipids & Breast Cancer Prevention

MCC member Lisa Yee, MD, and Program Co-Leader Steven Clinton, MD, PhD, have discovered a novel “genetic by nutrient” interaction in breast carcinogenesis. By examining the relationship between dietary omega-3 fatty acids and signaling through the epidermal growth factor receptor 2 (HER-2/neu) (J Nutr 2005; 135(5):983-988), the team showed that overexpression of the HER-2/neu molecular subtype of breast cancer was associated with poor clinical outcome. Fish oil-based diets markedly suppressed HER-2/neu breast tumor incidence as well as tumor multiplicity and mammary gland dysplasia. These findings demonstrate a potent preventive effect of (n-3) PUFA on HER-2/neu-mediated mammary carcinogenesis.

Bioavailability of Tomato Carotenoids in Humans

MCC investigators conducted several landmark clinical trials to elucidate factors that modulate bioavailability of tomato carotenoids in humans. If tomato carotenoids are involved in human prostate carcinogenesis or other cancers, bioavailability is a critical process to understand. MCC researchers demonstrated that the correlation between estimated lycopene intake and blood concentrations in humans is often in the range of r=0.2 to 0.4, a poor correlation.

Collaborations

Molecular Carcinogenesis & Chemoprevention (MCC) is one of OSUCCC–James' six highly interactive cancer Research Programs. The programs comprise more than 200 leading scientists from 13 different colleges within OSU and affiliated academic institutions.

MCCR investigators collaborate with several OSUCCC Shared Resources, including 
Analytical Cytometry, Biomedical Informatics, Biorepository & Biospecimen, Proteomics, Pharmacoanalytical, Nucleic Acid, Biostatistics and Microarray.

Other collaborations include:

Intra-Programmatic Collaborations

  • Studies by MCC members Tatiana Oberyszyn, PhD, Tober, PhD, Traci Wilgus, PhD, and Kusewitt, PhD, are elucidating critical components of UV and chemical induced skin carcinogenesis. The team is documenting the distribution of E prostanoid receptors in unirradiated and UVB-exposed SKH-1 mouse skin, UVB impacts on E prostanoid receptor expression in murine skin, and how EP receptors’ differential expression suggests that each receptor may play a distinct role in skin tumor development (J Invest Dermatol 2006; 126(1):205-211; J Invest Dermatol 2007; 127(1):214-21; Mol Carcinog 2007; 46(8):711-5).
  • MCC members Christopher Weghorst, PhD, Bruce Casto, DrSc, and colleagues are examining the role of TGF in oral carcinogenesis and extending their observations to other malignancies. In a series of publications, the investigators reported TGF beta receptor polymorphisms’ impact on susceptibility to carcinogenesis and how the somatic mutation acquisition in the receptor provides cancer cells with a growth advantage when in the presence of TGF.  The acquired mutations are a new facet of TGF beta signaling in cancer and suggest that the TGF beta receptor may represent a potential target for inhibiting carcinogenesis. The investigators’ work also suggests that somatic acquisition of this variant is a critical event in early cancer development stages and is associated with field cancerization in head and neck cancers (JAMA 2005; 294(13):1634-1646.; Hum Mol Genet 2007; 16(24):3128-35).
  • MCC members Christopher Weghorst, PhD, Bruce Casto, DrSc, Peter Muscarella, MD, Susan Mallery, DDS, PhD, Li, PhD, and colleagues examined the role of p16 genetic alterations in carcinogenesis (J Mol Biol 2007; 373(4):990-1005: Biochemistry 2005; 44(40):13246-13256: Gene Expr 2008; 14(4):207-16: Carcinogenesis 2004; 25(2):263-8), particularly focusing on oral lesions (Cancer Epidemiol Biomarkers Prev 2008; 17(11):3179-87.). The study demonstrates the resemblance between chemically induced HCP tumors and their human counterparts in p16 genetic alterations, and it strongly supports utilizing the DMBA-induced HCP tumor model in evaluating novel p16-targeted therapy and prevention of human oral SCCs (Mol Carcinog 2008; 47(10):733-8).
  • MCC Co-Leader Steven Clinton, MD, PhD, and MCCRP member Klein, PhD, examined the role of cycloxygenase in bladder cancer using unique animal models. They employed microarray gene analysis to determine COX-2 overexpression effects on gene expression profiles in the urinary bladder. Statistical analysis revealed that 70 genes were upregulated and 60 were downregulated by twofold or more in bladders from transgenic compared to wild-type mice. Expression Analysis Systematic Explorer (EASE) analysis revealed that genes associated with Immune/Stress Response and Cell Cycle/Proliferation biological processes were overexpressed in the transgenic mice. Relevant downregulated genes included three transforming growth factor (TGF)-beta related genes, Tgfb2, Tgfb3 and Tgfbi.

The growth factor epiregulin was the most highly induced gene among those validated by qRT-PCR in mouse bladders, overexpressing COX-2 in parallel with increased staining for the proliferative marker Ki67. Prostaglandin E2 directly induced the epiregulin mRNA  expression in bladders from wild-type FVB mice ex vivo. The team also determined that recombinant epiregulin increased both cell proliferation and Erk phosphorylation in UMUC-3 bladder cancer cells. The results indicate that mouse urinary bladder response to elevated COX-2 expression includes enhanced inflammatory response and cell proliferation induction. The growth factor epiregulin may play a role in bladder carcinogenesis and may serve as a novel target for the prevention and treatment of bladder cancer (Mol Carcinog 2009; 48(1):1-13). 

  • MCC member Douglas Kinghorn, PhD, DrSc, collaborated with program colleagues Steven D’Ambrosio, PhD, Robert Brueggemeier, PhD, and Michael Pereira, PhD, to identify bioactive agents from several nontraditional tropical foods, like avocado fruit (Semin Cancer Biol 2007; 17(5):386-94), Mexican tomatillos (FEBS Lett 2007; 273(24):5714-5723), Morinda citrifolia (J Nat Prod 2005; 68(12):1720-1722; J Nat Prod 2005; 68(4):592-595) and constituents of the roots and stolons of licorice (J Agric Food Chem 2007; 10(102):230-240). Focusing on breast cancer, the team identified Xanthones from mangosteen with aromatase inhibitory activity (J Nat Prod 2008; 71(7):1161-6; J Nat Prod 2006; 69(4):700-3).
  • MCC member Ching-Shih Chen, PhD, developed a novel phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, (S)-HDAC-42. In collaborative chemoprevention studies using the TRAMP model of prostate carcinogenesis, Dr. Chen and MCC Co-Leader Steven Clinton, MD, PhD, demonstrated a potent ability to inhibit prostate tumor progression and stimulate the differentiation of aggressive cancers into a less aggressive histopathologic subtype (Cancer Res 2008; 68(10):3999-4009).
  • MCC member Ching-Shih Chen, PhD, has studied the potential for OSU-03012 to act as a chemopreventive agent for oral carcinogenesis has been studies in collaboration with fellow program member Steven D'Ambrosio, PhD. The relationship between cell cycle inhibition and apoptosis induced by OSU03012 was investigated in human oral cancer cell lines. The authors showed that OSU03012 has potent anti-proliferative and apoptotic activity against premalignant and malignant human oral cells through activation of Erk1/2, and Cdks. OSU0312 may provide unique opportunities for cancer prevention and sensitization of cancer cells to S-phase modalities (Int J Cancer 2008; 123(12):2923-30.).
  • MCC members Ching-Shih Chen, PhD, Klein, PhD, and Program Co-Leader Steven Clinton, MD, PhD, collaborated to evaluate OSU-03012’s role in prostate carcinogenesis. Initial studies underscored the role of 3-phosphoinositide-dependent protein kinase-1/Akt signaling in celecoxib-mediated in vitro antiproliferative effects in prostate cancer cells (Cancer Res 2004; 64(4):1444-1451). A subsequent study (Toxicol Pathol 2007;35(4):549-61) examined the mechanistic link between Akt signaling and prostate carcinogenesis by evaluating the chemopreventive relevance of inhibiting this pathway in the transgenic adenocarcinoma of the model prostate mouse with OSU03012. The drug treatment significantly decreased prostatic lesion progression based on the reduced weight of all four prostate lobes as well as the grade of epithelial proliferation. The team concluded that targeting the PDK1/Akt pathway has chemopreventive relevance in prostate cancer and causes other in vivo effects mediated in part by altering bioenergetic signaling.
  • MCC member Gary Stoner, PhD, and program colleague Tong Chen, MD, showed that nitrate oxide synthetase A is overexpressed during esophageal carcinogenesis and generates a high NO concentration that is associated with esophageal carcinogenesis progression in response to the carcinogen NMBA. They also demonstrated that the agent PBIT, a selective INOS inhibitor, prevented esophageal cancer progression. PBIT reduced NO and preneoplastic production as well as papillomatous esophageal lesions compared to untreated controls. The studies suggest that INOS plays a role in tumor esophageal carcinogenesis and that it's inhibition is a potential target for chemopreventive agents (Cancer Res. 2004 May 15;64(10):3714-7; Mol Carcinog 2004; 40(4):232-40).
  • MCC members Gary Stoner, PhD, Susan Mallery, DDS, PhD, and Kresty, PhD, examined early molecular events in the development of N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis and of the effects of chemopreventive agents on these events. Results indicated that phenylethyl isothiocyanate (PEITC) treatment had a genome-wide modulating effect on NMBA-induced gene expression. Samples obtained from animals treated with PEITC alone or cotreated with PEITC + NMBA were more similar to controls than to samples treated with NMBA alone.  PEITC also had a protective effect on NMBA-induced preneoplastic lesions in the rat esophagus (Cancer Res 2007; 67(13):6484-92; Toxicol Lett 2005; 155(3):427-36).
  • MCC member Tatiana Oberyszyn, PhD, and program colleagues studied reactive oxygen species (ROS) inhibition during the UVB-induced inflammatory response as a target for cancer prevention. DNA adducts such as 8-oxo-dG are known contributors to skin cancer development. The 8-oxoguanine DNA glycosylase (OGG1) enzyme repairs 8-oxo-dG adducts, suggesting that enhancing its activity in the skin might increase 8-oxo-dG repair, preventing skin cancer development. The investigators used the SKH-1 murine model to examine the effect of topically applied OGG1 on UVB-induced skin cancer development. A liposome-encapsulated OGG1 enzyme formulation reduced tumor size and dramatically reduced tumor progression. The results suggest that oxidative DNA damage contributes to UVB-induced skin tumor progression and that a topical formulation containing OGG1, perhaps in conjunction with other DNA repair enzymes such as T4 endonuclease V, could be used in populations at high risk for skin cancer development (Photochem Photobiol 2008; 84(2):317-21.).
  • MCC members Gary Stoner, PhD, Kresty, PhD, Tong Chen, MD, and colleagues are investigating the potential of black raspberries and other berry types to prevent esophageal cancer. The investigators have shown that incorporating freeze-dried berries into healthy diets has significant preventive activity in rodent models. Black raspberries inhibit N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis with a parallel down-regulation of the tumor promoting enzymes cyclooxygenase-2 and inducible nitric oxide synthase, as well as by altering carcinogen detoxification enzymes (Carcinogenesis 2006; 27(11):2301-7; Cancer Res 2006; 66(5):2853-9; Nutr Cancer 2006; 54(1):47-57; Carcinogenesis 2006; 27(8):1617-26).
  • MCC members Steven D’Ambrosio, PhD, and program colleagues demonstrated the growth inhibition of premalignant and malignant human oral cell lines by extracts and components of black raspberries. (Nutr Cancer 2005; 51(2):207-17).  MCCRP member Susan Mallery, DDS, PhD, extended this work and employed cell lines isolated from human oral SCC tumors to investigate the effects of a freeze-dried black raspberry ethanol extract on cellular growth characteristics associated with a transformed phenotype such as sustained proliferation, angiogenesis induction and high-level production of reactive species. The results demonstrated that berry extracts suppress cell proliferation without perturbing viability, inhibited translation of the complete angiogenic cytokine vascular endothelial growth factor, suppressed nitric oxide synthase activity, and induced both apoptosis and terminal differentiation. These data suggests that berries are a promising candidate for use as a chemopreventive agent in persons with oral epithelial dysplasia (Nutr Cancer 2006; 54(1):58-68).
  • MCC members Mark Failla, PhD, and Steven Schwartz, PhD, utilized a novel in vitro Caco-2 human intestinal cell system developed at OSU (J Agric Food Chem 2006; 54(7):2780-2785) to study the dramatic impact of lipids on carotenoids absorption. The studies demonstrated that tomato-derived carotenoid absorption can increase by more than 100-fold simply by changes in the fat content of a meal.
  • MCC Co-Leader Steven Clinton, MD, PhD, and program colleague Steven Schwartz, PhD, were the first to demonstrate the broad array of tomato-derived carotenoids in the human prostate. Their collaborative epidemiologic studies suggest an inverse relationship between plasma lycopene and prostate cancer risk lycopene (Cancer Epidemiol Biomarkers Prev 2004; 13(2):260-269; Nutr Cancer 2005; 53(2):127-34).
  • MCC Co-Leader Steven Clinton, MD, PhD, and program member Steven Schwartz, PhD, have shown that lycopene isomers show a dramatic absorption increase with heat processing of tomatoes, as is done in many food product preparations such as juice and sauces (Br J Cancer 2007; 29:1-7). Additional studies show that tomato phytochemcial absorption is critically impacted by the composition of a meal.
  • Modern genetic and breeding studies have provided various tomato types and colors that are enriched in carotenoid cis-isomers. Clinical studies by MCC Co-Leader Steven Clinton, MD, PhD, and program colleague Steven Schwartz, PhD, have shown the cis-isomers are more effectively absorbed than all trans isomers (J Agric Food Chem 2007; 55(4):1597-603). Thus, specific tomato varieties may have an advantage in future cancer prevention studies based on isomer patterns.
  • MCC Co-Leader Steven Clinton, MD, PhD, and his team assessed the ability of food combinations to have additive or synergistic effects for prostate cancer prevention. Using precisely defined and nutritionally complete diets, the investigators found a significant increase in survival of rats and reduced prostate tumorigenesis progression when fed a combination of tomato powder combined with broccoli powder (Cancer Res 2007; 67(2):836-43).
  • MCC Co-Leader Steven  Clinton, MD, PhD, MMCRP member Steven Schwartz, PhD, and their team conducted a human feasibility study focusing on a combination of soy and tomato products as a food-based intervention for men with prostate cancer and a rising PSA, but currently undergoing observation rather than active therapy (Nutr Cancer 2008; 60(2):145-54). The investigators observed a significant reduction in PSA or PSA velocity. Additionally, the study demonstrated a reduction in serum VEGF, a critical angiogenic growth factor found to be inhibited by soy phytochemicals in in vitro and rodent studies (J Nutr Biochem 2007; 18(6):408-17).

Inter-Programmatic Collaborations

  • MCC member Tatiana Oberyszyn, PhD, is collaborating with Molecular Biology & Cancer Genetics Research Program member Amanda Toland, PhD, to define genetic defects in mouse models that mimic adult transplant recipients in order to study the effect of immunosuppressive drugs and UV light on SCC development. UV-induced tumors from six treatment groups, control, tacrolimus (Tac), rapamycin (Rap), cyclosporine (CsA), mycophenolate mofetil (MMF), and Rap plus CsA, were evaluated by array comparative genomic hybridization. Mouse SCCs appear to show: (1) similar genomic aberrations as reported in human SCCs and offer the ability to identify genomic changes associated with specific and combinatorial drug effects; (2) fewer aberrations seen in tumors of mice treated with MMF or Rap; (3) tumors from Tac-treated animals showed the highest number of changes; and  (4) Calcineurin inhibitors did not cluster together by their genomic aberrations, indicating their contribution to UV-mediated carcinogenesis may be via different pathways. The combination treatment (Rap plus CsA) did not cluster with either treatment individually, suggesting it may influence SCC tumorigenesis via a different mechanism. (Genes Chromosomes Cancer 2009; 48(6):490-501).
  • MCC member Douglas Kinghorn, PhD, DrSc, and Experimental Therapeutics Research Program members John Byrd, MD, and Michael Grever, MD, demonstrated that a novel plant-derived compound called Silvestrol has B-cell selective activity in chronic lymphocyte lymphocytic leukemia and acute lymphoblastic leukemia both in vitro and in vivo in animal models (Blood 2009; 113(19):4656-66). These data indicate that Silvestrol has efficacy and a high degree of safety in studies. Silvestrol causes early reduction in Mcl-1 expression because of translational inhibition with subsequent mitochondrial damage. In vivo, Silvestrol causes significant B-cell reduction in Emu-Tcl-1 transgenic mice, and it significantly extends survival of 697 xenograft SCID mice without discernible toxicity. These data indicate Silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias.
  • MCC member Douglas Kinghorn, PhD, DrSc., is the principal investigator of a collaborative, multidisciplinary P01 entitled, “Discovery of Anticancer Agents of Diverse Natural Origin” (P01 CA125066), funded by the National Cancer Institute (2007-2012).  The primary objective of the project is to discover new, natural-product anticancer agents from tropical plants (J Nat Prod 2007; 70(6):954-961; J Nat Prod 2007; 70(3):372-377; J Nat Prod 2007; 70(12):2049-2052; Tetrahedron Lett 2007; 48(10):1849-1853; Org Lett 2005; 7(25):5709-5712: Bioorg Med Chem Lett 2007; 17(1):109-12), to aquatic cyanobacteria (Protein Eng 2006; 14(4):960-972) and filamentous fungi.
  • MCC member Ching-shih Chen, PhD, and program colleagues are collaborating with numerous OSUCCC investigators  to identify specific regulatory defects in intracellular signaling during carcinogenesis in order to develop selective chemopreventive agents. Dr. Chen and this collaborative team are utilizing sophisticated computerized modeling to direct engineering of analogues that selectively disrupt defective or overexpressed cellular targets that emerge during carcinogenesis.
  • MCC member Ching-Shih Chen, PhD, and MCCRP investigators were the first to report that celecoxib’s ability to enhance apoptosis in prostate cancer cells is, in part, independent of COX-2 inhibition (J Natl Cancer Inst 94: 585, 2002; Cancer Res 2004; 64(12):4309-4318) and directly caused by AKT signaling blockage via PDK-1. The team subsequently chemically manipulated the structure to create a series of analogues with increasing ability to enhance the proapoptotic bioactivity. The PDK-1 inhibitor, named OSU-03012, was optimized and has undergone preclinical testing through the Rapid Access to Intervention Development program at the National Cancer Institute. Phase I clinical trials of OSU-03012 opened at the OSUCCC in fall 2009.

OSU-03012’s potential has been illustrated by preclinical studies for cancers of various tissues. Dr. Chen and Experimental Therapeutics Research Program members John Byrd, MD, and Michael Grever, MD, examined hematologic malignancies, with OSU-03012 showing cytotoxic activity for primary CLL cells and transformed B-cell lymphoma independent of caspase and Bcl-2 mechanisms (Blood 2005; 105(6):2504-2509). Further studies showed synergistic interactions between imatinib mesylate and OSU-03012 in overcoming imatinib mesylate resistance (Blood 2005; 105(10):4021-7).  The mechanism was explored and focuses upon the targets of endoplasmic reticulum stress and Akt with OSU-03012 and gefitinib or erlotinib (Cancer Res 2008; 68(8):2820-30).

  • MCC member Robert Brueggemeier, PhD, and Cancer Control Research Program member Charles Shapiro, MD, have studied OSU-03012 and demonstrated the ability to sensitize estrogen receptor-negative breast cancer cells to tamoxifen (Mol Cancer Ther 2008; 7(4):800-8). Further studies showed that OSU-03012 can overcome trastuzumab resistance in HER2-overexpressing breast cancer cells via phosphoinositide-dependent kinase-1 inhibition (Mol Pharmacol 2006; 70(5):1534-41).
  • MCC member Robert Brueggemeier, PhD, and Cancer Control Research Program member Charles Shapiro, MD, have observed that thiazolidenediones mimic glucose starvation in facilitating Sp1 degradation through the upregulation of {beta}-TRCP (Mol Pharmacol 2009; in press), suggesting that the compounds may act in part by the disruption of cancer cell energy metabolism. Similar anticarcinogenic activity has been noted for breast cancer studies with Dr. Brueggemeier and Dr. Shapiro (Mol Pharmacol 2005; 67(4):1342-8).
  • The MCC, in collaboration with the Molecular Biology & Cancer Genetics Research Program, co-sponsors the Autophagy Journal Club, a monthly meeting focusing on Autophagy and Cancer. The AJC is coordinated by MCCRP member  Ibba, PhD (?). The program is open to all OSUCCC members and their interested laboratory team members

Inter-Institutional Collaborations

  • University of Cincinnati, Laboratory of Yi Zheng, PhD: MCCRP members are collaborating with the University of Cincinnati’s Yi Zheng, PhD: to study the function and mechanism of regulation of the Rho family small GTP-binding proteins of Ras super-family, with a particular focus upon hematopoietic lineage cells.
  • University of Cincinnati, Laboratory of Grimes, PhD: MCC members are collaborating with the University of Cincinnati’s Grimes, PhD: to study growth factor independence-1 (Gfi1) transcription factor and leukemogenesis. Dr. Grimes focuses on characterization of oncoproteins and tumor suppressors involved in molecular mechanisms of transformation, and has also provided a large set of targets for chemoprevention.
  • Cincinnati Children’s Hospital Medical Center, Laboratory of Qishen Pang, PhD: MCC members are collaborating with the Cincinnati Children’s Hospital Medical Center’s Qishen Pang, PhD, (?), to study Fanconi anemia, reactive oxygen and leukemogenesis. Dr. Pang focuses on the genetic syndrome FA and aspects of how reactive oxygen species impact leukemogenesis, particularly focusing upon regulation of the cell cycle and apoptosis. 

     

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) 300 W. 10th Ave. Columbus, OH 43210 Phone: 1-800-293-5066 | Email: jamesline@osumc.edu