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Targeting Cellular Processes as a New Approach for Cancer Treatment Ru Chih Huang, PhD Professor of Biology Johns Hopkins University Oct 24th 2009, CAPA Symposium, Gaithersburg, MD 1 CURRENT STATUS “In a long drive to cure cancer, advances have been elusive” ~Gina Kolata New York Times National , Front Page - April 24th, 2009 2 “Is cancer just an impossibly hard problem? OR Is the United states, the only country to invest so much in Cancer research*, making fundamental mistakes in the way it fights cancer?” The answer is “YES” on both counts – Gina Kolata. *$105 Billion from NCI and billions more from drug companies and philanthropies 3 A Thorough Trial Takes Time and Money $10x106 $20x106 $45x106 4 Cancer Drug Rise in Popularity 5 CLINICAL TRIAL RESULT FOR TREATMENT OF BREAST METASTASIZED CANCER (2007 – 2009) Median Time (Months) Treatment Cancer progression to start again Patient survival Avastin plus Paclitaxel 11.3 months 26.5 months Paclitaxel alone 5.8 months 24.8 months 1. Severe Side Effect: 5 or 6 out of 363 died from drug Avastin 2. Received accelerated approval (Progression-Free Survival) from FDA 3. Avastin: $2.3 billion in Sales, 2007 Genentech 4. Breast cancer treatment $7,700/ month 5. FDA Panel supports Avastin to treat type of brain cancer despite the FDA’s own staff reviewers saying that there was a lack of compelling evidence that the drug worked for 6 that use (April 1st, 2009; New York Times). Oncogenic pathway/Targeting with specific Protein Inhibitor Targeted by specific protein inhibitor Months Days Heterogenous Tumor cells regain growth in facing drug resistances 7 Common Drug Side Effects 1. Alopecia *2. Diarrhea, Nausea, Vomiting (Effects of the dividing cells of Gastrointestinal tract) *3. Anemia, and Immune deficient (Effects of dividing cells of bone marrow 4. Fatigue 5. Hypertension 6. Skin Condition 8 Most Therapies by Targeting Specific Growth Protein Factors Have Limited Impact By Andrew Pollack Forty years’ war Small Victories, High Prices 1. Since most tumors are fueled by numerous often redundant, genetic anomalies 2. Only a trickle of new cancer drugs make it to market. Last year there were two and this year there has been only one. Tarceva which costs $3500 a month for treatment of pancreatic cancer because it improved survival for 12 days. 9 Combination Therapy Standard of care for Glioblastoma since 1978 (Surgery, Radiation, Chemotherapy) Without treatment Radiation alone Radiation plus Temozolomide ± Surgery 14 weeks 36 weeks 62.5 weeks Ref: 1. Predictive and Prognostic Markers in Human Glioblastomas. Palanichamy K, Erkkinen M, Chakravarti A. Current treatment options in Oncology 2006, 7:490-504 2. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. Stupp R. et. Al. N. Engl J. Med 2005, 10 352(10): 987-996 A New Approach Search for a combination drug regimen which is able to: • eliminate the entire population of heterogeneous cancer cells, •stop the growth of the circulating tumor cells, micro- and macrometastasis without lasting side effects to the host. “Targeting cellular processes that are operating on a different scale in cancer cells” 11 Cell Organelles – Mitochondrion for High ATP Synthesis and Nucleus for High Gene Expression 12 Cellular Processes Synthesis of RNA In Normal cells In Cancer cells + ++++ Synthesis of Proteins + For different proteins, limited time period ++++ Continuous for oncogenic proteins 13 Structure Diagram of a Mitochondrion Synthesis of ATP Normal Cells + Cancer cells ++++ Q: Ubiquinone C: Cytochrome C 14 Combination Drug Regimen Targets Three Cellular Processes Cancer Cells Drug Design Some unique features of cancers Goal Characteristics of the drug selected High rate of transcription, most growth related genes are over-expressed Names of the drugs Lower the synthesis of As global Terameprocol large group of mRNAs transcription (M4N) in and proteins which are inhibitors which Phase I/II clinical over-expressed in can suppress the trial cancers promoter activities of many oncogenes High rate of cellular Reduce the level of As mitochondrial metabolism with high energy energy in cancer cells uncouplers for demands prevention of ATP synthesis. Resistance to aging and cell Induce rapid cell death As blockers of death with pro-apoptotic by activating the process PI3/AKT signal proteins inactivated of apoptosis transduction pathway. Efficacies of the combination Drug Regimen Three drugs have been found to be strongly synergistic in treating a variety of cancer cells in culture and in human prostate cancer xenografts , eliminating orthotropic cancer implants and metastasis in lungs. 100% of the treated mice are disease free and continuing to live beyond 300 days Phase II Clinical Trial in preparation 15 M4N EM1421, Terameprocol Sp1 GGGCGGG Consensus M4N is a global Transcription Inhibitor. Inhibition is by allosteric modulation of DNA unsuitable for Sp1 binding. Ref: J Med Chem (1998) 41:3001-3007 Antiviral Res (2000) 47: 19- 28 Antiviral Res (2003) 58: 35- 45 16 M4N in major groove NMR studies have pointed out several other NDGA derivatives (P4N, Maltose M3N) interact with SP1 DNA (SPD) also in major groove 12-mer-SPD-P4N crystal as reflected by a 10Å Increase in the C-axis: Widened major groove and exposed minor groove 172005. J. Mol. Biol. 349, 731-744, Sp1 Expression is Upregulated in Many Cancers and is Often a Significant Predictor of Survival Fig. 6 from Masashi et.al Clin. Cancer Res. 2006: 12 (21) 6395-6402 Fig. from Jiang et.al Cancer Epid. Biomarkers Prev. 2008:17 (7) 1648-52 Fig. 4B from Wang et.al Clin. Cancer Res. 2003: 9 (17) 6371-6380 18 Broad Spectrum Effect of M4N on control of Cancer Cell Growth 1. M4N is one drug with many targets. 2. M4N is also one of multiple drugs with individual single targets. 3. M4N has the unique advantage for targeting heterogeneous population of tumor cells. M4N M4N Cdc2 G2/M Deregulated Cell Division HIF-1α Glycolysis M4N HIF-1α* M4N MDR1 PGp CANCER CELL SURVIVAL Drug Resistance Vascularisation Radiation Resistance In Hypoxia Region of The Solid Tumor Activated AKT AKT * Degradation of HIF-1α protein VEGF M4N HIF-1α M4N M4N 19 There are 22,633 known genes in the Ensemble Human Genome database. 52.5% of these genes, including Sp1, contained the Sp1 binding motif 5’GGGCGG3’ in their immediate (500 bp) upstream region. A.K. Todd and S. Needle N.A.Res. 2008 36 (8) 2700-2704 M4N is able to inhibit a majority of these over-expressed genes in cancer cells. 20 21 CONTRIBUTORS Lab of Collaborators Professor J.R. Hwu Chem. Dept. Tsing Hwa University R.B. Bates Chem. Dept Univ. of Arizona A. L. DeLucia Dept. Microbiology & Biochemistry Northesten Ohio Univ. College of Medicine S.Kokpol Chem.Dept. Chulalongkorn Univ. Y.C.Lee Biology Dept. JHU Y. Ito Lab of Physical Chemistry NHLB, NIH J.N. Brady Lab of Mol.Virology NCI H.S. Chen Inst. Of Medicinal Biotech. Chinese Academy of Science Y.Z. Cao Chinese Academy of Science N. Khanna Univ. of Maryland Medical School H. Farzadegan Epidemiology Dept. JHSPH T. C. Wu Pathology Dept. JHMI E.N. Moudrianakis Biology Dept. JHU Richard Cone Biophysics Dept. JHU E. Freire Biology Dept. JHU Research Team David Mold, MD, PhD Ibrahim Abd-Elazem, PhD Kotohiko Kimura, MD, PhD John Gnabre, PhD Jong Ho Chun, MD Paul Giza Tiffany Jackson Denise Lin Shruthi Ramkumar Kevin Ho Chris Ruland Murwan Abdallah Alexandra McMillan Richard Park JHU Ph.D. 2002 Tom Chang JHU Ph.D. 2005 John Heller JHU Ph.D. 2002