Molecular Therapeutics Program Activities and Selected Scientific Reports
Alan Eastman, PhD and Lionel D. Lewis, MB. BCh., MD co-direct Molecular Therapeutics, which is one of six pivotal clinical translational Research Programs at Norris Cotton Cancer Center. The 30 members of Molecular Therapeutics come from eight academic Departments at The Geisel School of Medicine and at Dartmouth College for the purpose of integrating information and findings about Cancer Molecular Therapeutics. This NCCC Program has regular monthly meetings and many other activities during the year.
Molecular Therapeutics contributes to the academic dialogue at Dartmouth by sponsoring speakers and hosting the Lipogenesis Interest Group. Members contribute frequently to other Dartmouth seminar series including the Cancer Center Grand Rounds, Pharmacology & Toxicology seminars and Chemistry colloquia.
In the clinical arena, members of Molecular Therapeutics are embedded in Cancer Center Oncology Groups/Tumor Boards at our Dartmouth-Hitchcock Medical Center location in Lebanon, New Hampshire. Todd Miller, PhD is the Scientific Director of the Comprehensive Breast Program and Breast Tumor Board. Lionel D. Lewis directs the Early Phase Trial Clinical Oncology Group and works with Alan Eastman PhD, Yolanda Sanchez, PhD, Chris Amos PhD, Konstantin Dragnev MD and Jack Hoopes DVM, PhD who constitute the executive committee of the Early Phase Trial Clinical Oncology Group.
Journal clubs and research-in-progress presentations enrich the advancement of science and provide opportunities for discussions. The Cancer Biology and Molecular Therapeutics Journal Clubs meet weekly and Molecular Therapeutics faculty members are regular attendees.
Regionally, Molecular Therapeutics is active with the University of Vermont and University of Massachusetts Medical Center in sponsoring a symposium on genomic stability. Molecular Therapeutics members Yolanda Sanchez and Alan Eastman are past presenters. The regional clinical trials network New England Oncology Network (NEON) provides additional opportunities for collaboration.
Nurturing a supportive and challenging academic community for Molecular Therapeutics members is a premier NCCC priority, and program activities reflect that in their mentoring, teaching, grant writing, and recruitment. Alexey Danilov, MD, PhD and Kerrington Smith, MD were recruited into the program for their clinical translational focus. Additionally the recent recruitments of Todd Miller, PhD, and Manabu Kurokawa, PhD were key hires to amplify the program’s strengths in translational research.
Turning to teaching, Alan Eastman is the director of the Graduate Program in Experimental and Molecular Medicine (PEMM) and Michael Spinella, PhD directs the Cancer Biology and Molecular Therapeutics theme within PEMM. Many of Molecular Therapeutics faculty members teach both graduate students at Dartmouth and medical students from Geisel School of Medicine. Senior program members participate in mentoring committees for all junior faculty members.
At the national level, Molecular Therapeutics director Alan Eastman serves as Treasurer for the Cancer Molecular Therapeutics Research Association that holds annual meetings. Lionel D. Lewis is the appointed vice chair of the Alliance PPP committee with responsibilities for furthering and overs
2013 Selected Scientific Progress & Achievements
Work in the Program identified multiple means by which cancer cells can acquire necessary fatty acids for proliferation and survival. In addition to de novo synthesis, many tumor cells secrete lipoprotein lipase to capture circulating lipids and/or express CD36, the channel for fatty acid uptake. We have performed a proof-of-principle clinical trial demonstrating that conjugated linoleic acid, considered a nutraceutical, suppressed S14 expression (a regulator of fatty acid synthesis) in human breast cancer tissue (McGowan et al, Breast Cancer Res Treat, 2013).
We have identified three different pathways through which the Chk1 inhibitor MK-8776 enhances chemotherapy, the most effective combination occurring when gemcitabine or hydroxyurea stall replication forks and induce Chk1-dependent homologous recombination. In addition, Chk1 inhibition is highly effective as monotherapy in a subset of cancer cell lines (Thompson and Eastman, Brit J Clin Pharm 2013).
We have Identified a novel pathway whereby the E3 ligase MDM2 targets a second ligase HUWE1 for degradation, and vice versa. Whereas MDM2 is well known to target degradation of p53, HUWE1 is better known for its role in the degradation of the BCL2 family member MCL1 (Kurokawa et al, Sci Signal 2013).
We have identified a variety of strategies to overcome stroma-mediated resistance of chronic lymphocytic leukemia (CLL) to the BCL2 inhibitor navitoclax and other chemotherapy drugs; one drug, gossypol, completely reversed resistance to navitoclax. We performed a proof-of-concept clinical trial in CLL patients demonstrating that vincristine activated the signaling pathway that is necessary for sensitization of the cells to BCL2 inhibitors (Bates et al, Mol Cancer Therap 2013; Soderquist et al, Leukemia 2013).
We have defined the changes in the phosphoproteome that occur upon inhibition of aurora kinase and polo-like kinase and developed proteomic technology to identify phosphoproteins as biomarkers for analysis of nonsmall cell lung cancer (Schweppe et al, J Proteomics 2013).
We have discovered that the proteasome inhibitor bortezomib (Velcade™) needs to inhibit two different proteolytic activities to kill effectively cancer cells. We developed a series of novel proteasome inhibitors selective for each of the three protease sites and demonstrated the relative importance of inhibiting each site for cytotoxic activity (Shabaneh et al, PlosOne 2013).
The synthetic triterpenoid, 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid (CDDO-Me), prevented tumor development in models of estrogen receptor-negative breast cancer, pancreas cancer and lung cancer either alone or in combination with vorinostat or rexinoids (Tran et al 2013).
Novel drug combinations and strategies have been developed that deregulate cyclin D and E leading to inhibition of NSCLC cell lines and xenografts in cyclin E transgenic mice. The combination of bexaratene plus erlotinib has been translated into proof-of-concept and phase II clinical trials (Ma et al, Mol Cancer Therap, 2013).
We have demonstrated the feasibility of analyzing the phosphoproteome from freshly-isolated non-small cell lung cancers as potential biomarkers for future therapeutic decisions (Schweppe et al, J Proteomics 2013).
Dr. Kisselev’s research focuses on the proteasome, in particular designing novel inhibitors for the treatment of relapsing, refractory multiple myeloma and solid tumors. The proteasome has three types of active sites. Chymotrypsin-like sites are the most important for protein breakdown and have long been considered the only suitable targets for antineoplastic drugs. However, Dr. Kisselev has demonstrated that inhibitors of trypsin-like sites sensitize malignant cells to inhibitors of the chymotrypsin-like sites (Geurink et al J Med Chem 2013).
Dr. Lewis has been Dartmouth PI on a first in man study of the combination of cyclophosphamide pretreatment with a humanized immunoconjugate of an anti-EpCAM antibody linked to two molecules of IL-2. The study hypothesis was that cyclophosphamide would increase T cell numbers facilitating the hu KS-IL2 effect of NK cell generation and activation in the microenvironment of tumors expressing EpCAM, increasing cell cytotoxicity. This study established the MTD of the cyclophosphamide-huKS-IL2 combination (mainly limited by IL-2 side effects), the pharmacokinetics of huKS-IL2 and its systemic immunologic and immunogenic effects in patients with solid tumors (BMC Cancer. 2013;13:20) .
A randomized, placebo-controlled, double-blinded study to assess the effects of repeated oral dosing of pazopanib on the QTc interval was conducted (Lewis, PI). A small (4.4 msec greater than placebo) but clinically insignificant effect of pazopanib on QTc was observed, which was not related to the concentration of pazopanib or its metabolite (Cancer Chemother Pharmacol 2013 71; 565-73).
2012 Selected Scientific Accomplishments
- Further improved outcome in localized, and locally advanced, pancreatic ductal adenocarcinoma, by combining cetuximab with gemcitabine and radiotherapy in neo-adjuvant therapy. At surgery, marginnegative resection rates were high, and some locally advanced tumors were down-staged, to allow for complete resection, with encouraging survival. Pathological complete responses also were observed. (Pipas JM et al, 2012)
- Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, Tsongalis GJ, Colacchio TA, Gordon SR, Sutton JE, Srivastava A, Smith KD, Gardner TB, Korc M, Davis TH, Preis M, Tarczewski SM, Mackenzie TA, Barth RJ, Jr. (2012, In press). Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. PMC Journal - In Process
- Determined that the novel Chk1 inhibitor MK-8776 dramatically sensitizes tumor cells to hydroxyurea and gemcitabine in a sequence-dependent manner; the same study established that some tumor cell lines are hypersensitive to MK-8776 alone and more sensitive to the combination with hydroxyurea, suggesting there may be a large therapeutic window for appropriately selected patients. (Montano R et al., 2012)
- Montano R, Chung I, Garner K, Parry D, Eastman A (2012). Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA damaging agents and antimetabolites. Mol Cancer Ther 11(2):427-438. PMC3277678 [Available on 2013/2/1]
- The synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), prevented tumor development in two models of estrogen receptor-negative breast cancer. (Kim EH et al, 2012, Tran K et al 2012)
- Kim EH, Deng C, Sporn MB, Royce DB, Risingsong R, Williams CR, Liby KT (2012). CDDOmethyl ester delays breast cancer development in BRCA1-mutated mice. Cancer Prev Res 5(1):89-97. PMC Journal - In Process
- Tran K, Risingsong R, Royce D, Williams CR, Sporn MB, Liby K (2012). The synthetic triterpenoid CDDO-methyl ester delays estrogen receptor-negative mammary carcinogenesis in polyoma middle T mice. Cancer Prev Res (Phila) 5(5):726-734.
- Determined that obesity in mice fed a western diet can be modulated significantly by differential aryl hydrocarbon receptor signaling. (Kerley-Hamilton JS et al, 2012)
- Kerley-Hamilton JS, Trask HW, Ridley CJ, Dufour E, Ringelberg CS, Nurinova N, Wong D, Moodie KL, Shipman SL, Moore JH, Korc M, Shworak NW, Tomlinson CR (2012, In press). Obesity is mediated by differential aryl hydrocarbon receptor signaling in mice fed a western diet. Environ Health Perspect. PMC Journal - In Process