Marciniak, Robert AnthonySchool of Medicine |
| 7/2004 - Present | Assistant Professor | University of Texas Health Science Center at San Antonio, Cellular & Structural Biology, San Antonio, TX |
| 7/2001 - Present | Staff Physician | South Texas Veterans Health System, San Antonio, TX |
| 7/2001 - Present | Assistant Professor | University of Texas Health Science Center at San Antonio, Medicine, San Antonio, TX |
| 7/2001 - Present | Staff Physician | Cancer Therapy & Research Center, San Antonio, TX |
| 7/2001 - Present | Staff Physician | University Hospital System, San Antonio, TX |
| 7/2000 - Present | Assistant in Medicine | Massachusetts General Hospital, Boston, MA |
| 7/1998 - Present | Clinical Assistant | Massachusetts General Hospital, Boston, MA |
| Year | Degree | Discipline | Institution |
| 2001 | Postdoctoral Fellowship | Molecular Biology | Massachusetts Institute of Technology Cambridge , MA |
| 1997 | Clinical Fellowship | Hematology-Oncology | Massachusetts General Hospital Boston , MA |
| 1994 | Residency | Internal Medicine | Massachusetts General Hospital Boston , MA |
| 1993 | Internship | Internal Medicine | Massachusetts General Hospital Boston , MA |
| 1992 | MD | Medicine | Harvard Medical School Boston , MA |
| 1991 | PhD | Biology | Massachusetts Institute of Technology Cambridge , MA |
| 1981 | BA | Biochemical Sciences (Summa Cum Laude) | Harvard College Boston , MA |
Molecular genetics of aging and cancer- My lab is interested in the molecular biology of aging and cancer. We have been taking a genetic approach to this process, and have been working to understand how a loss of function of a single gene can cause the human segmental progeroid disorder, Werner syndrome (WS). WS is of interest as it shows many features suggestive of accelerated aging. WS is a rare autosomal recessive disorder, first described by Otto Werner in 1904. Individuals are normal at birth, and the first manifestation of abnormality is a decrease in growth rate during adolescence. In the young adult, the syndrome begins to fully manifest with many symptoms suggestive of premature aging, including the development of bilateral ocular cataracts, skin ulcerations, diabetes, osteoporosis, ischemic heart disease and a variety of neoplasms. The median age of death is 47 years, and the cause of death is most often myocardial infarction or malignancy. The gene defective in WS, Wrn, encodes a predicted protein of 1432 amino acids with the seven signature motifs characteristic of DNA and RNA helicases, enzymes that unwind nucleic acids in an ATP-dependent and directionally-specific manner. Our earlier in human cells and in yeast implicated a role of Wrn in telomere processing. In recent years, we have refined a role of Wrn protein in telomere maintenance. We have developed a model of the Wrn protein in unwinding alternative DNA structures that form on replication protein A (RPA) coated filaments. RPA is a protein that is commonly used to package single stranded DNA that is generated during multiple processing events, including transcription, replication, and repair. Specifically we demonstrated that WS cells show increased sensitivity to arrest in response to genotoxic stress during the G0 phase of the cells cycle, due to deletion of telomere sequences occurring during repair of segregated dysfunctional telomeres by break induced replication (BIR). We have expanded these studies of the function of the role of Wrn protein in telomere maintenance to include its role in S-phase. We find that in WS mutant cells, similar to the deletion that occurs during BIR in non-dividing cells, deletion of telomere sequences occurs during repair of telomeres by homologous recombination. These studies have led to a novel finding telomeres are fragile sites. Fragile sites are regions of the genome that demonstrate increased rates of recombination and breakage under conditions of replication stress. Replication stress occurs naturally when damaged bases are encountered by the replication fork, and is induced experimentally by treatment with agents that cause replication fork stalling (such as hydroxyurea or aphidicolin). Telomere recombination shows the same genetic requirements as genomic fragile sites. Telomere recombination is increased by pharmacologic inhibition of ataxia telangectasia mutated related protein (ATR) or checkpoint kinase 1 (CHK1), and by inhibition of expression of these proteins usin |
| Date | Description | Institution | # Students |
| 11/2009 - 12/2009 | Rotation Student Supervision | UTHSCSA | |
| 5/2009 - Present | Membership on Supervising Committee | UTHSCSA | |
| 4/2008 - Present | Membership on Supervising Committee | UTHSCSA | |
| 7/2005 - Present | Fellowship Clinical Lecture Series | University of Texas Health Science Center at San Antonio | 12 students |
| This is a lecture series on the clinical management of patients with specific malignancies. I give lectures on the clinical management of pancreatic, hepatobiliary, and colorectal cancers. | |||
| 6/2003 - Present | Fellowship Research Lecture Series | University of Texas Health Science Center at San Antonio | 12 students |
| This course I developed with James Freeman, PhD, of the Department of Medicine/Division of Medical Oncology. Although not offered for course credit, it is a series of 12 lectures presented for Clinical Fellows in Hematology-Oncology. With the rise in use of molecularly targeted therapies in Hematology and Medical Oncology, it has become increasingly necessary for practicing oncologists to have a greater understanding of underlying molecular biology. The design of the lecture series was to provide a targeted review of topics in molecular and cellular biology at a level suitable for MD Clinical Oncology Fellows. The concept was to provide the "bench" background in the "bench to bedside" application of targeted therapies. | |||
| 1/2002 - Present | Post-Doctoral Student Supervision | University of Texas Health Science Center | |
Journal Article |
| Siddiqa A, Long LM, Li L, Marciniak RA, Kazhdan I. Expression of HER-2 in MCF-7 breast cancer cells modulates anti-apoptotic proteins Survivin and Bcl-2 via the extracellular signal-related kinase (ERK) and phosphoinositide-3 kinase (PI3K) signalling pathways BMC Cancer 2008 May;8:129-129. |
| Silva JM, Cavazos D, Donzis E, Friedrichs WE, Marciniak RA, deGraffenried LA. Akt-Induced Tamoxifen Resistance is Associated with Altered FKHR Regulation Cancer Investigation 2007 Jan;. |
| Kazhdan I, Long L, Montellano R, Cavazos DA, Marciniak RA. Targeted gene therapy for breast cancer with truncated Bid Cancer Gene Ther 2006 Feb;13(2):141-149. |
| McNabb DS, Reed R, Marciniak RA. Dual luciferase assay system for rapid assessment of gene expression in Saccharomyces cerevisiae Eukaryot Cell 2005 Sep;4(9):1539-1549. |
| Marciniak RA, Cavazos D, Montellano R, Chen Q, Guarente L, Johnson FB. A novel telomere structure in a human alternative lengthening of telomeres cell line Cancer Res 2005 Apr;65(7):2730-2737. |
| Kazhdan I, Marciniak RA. Death receptor 4 (DR4) efficiently kills breast cancer cells irrespective of their sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) Cancer Gene Ther 2004 Oct;11(10):691-698. |
Abstract |
| Siddiqa, A, Cavazos, D, Chavez, JB, Long, L, Marciniak RA. Telomeres are fragile sites; 2009 Jan. (Gordon Conference: Chromosome Dynamics, Barga, Italy). |
| Siddiqa A, Cavazos D, Chavez JB, Long L, Marciniak RA. Dysfunctional telomeres cause senescence if there is failed repair by homologous recombination; 2009 Jan. (Keystone Conference on Telomere Biology and DNA Repair, Ashmore, Australia). |
| Ruparel S, Freidrichs W, Montellano R, Marciniak RA, DeGraffenried L. Role of the Catalytic Subunit of Telomerase in Stress Resistance and its Regulation by the Akt Pathway in Prostate Cancer; 2008 Jan. (Annual Meeting of American Association for Cancer Research. San Diego, CA). |
| Siddiqa , Cavazos D, Chavez JB, Marciniak RA. Telomeres are fragile sites; 2008 Jan. (Cold Spring Harbor Meeting on the Molecular Genetics of Aging, Cold Spring Harbor, NY). |
| Siddiqa A, Chavez J, Cavazos D, Long K, Marciniak RA. In Werner syndrome the telomere genotoxic clock runs fast; 2008 Jan. (Cold Spring Harbor Meeting on the Molecular Genetics of Aging, Cold Spring Harbor, NY). |
| Ruparel S, deGraffenried LA, Friedrichs W, Montellano R, Marciniak RA. Role of Telomerase in Prostate Cancer Cells; 2007 Jan. (98th Annual Meeting of the American Association for Cancer Research, Los Angeles, CA). |
| Ruparel S, DeGraffenried L, Freidrichs W, Montellano R, Marciniak RA. Role of Telomerase in Prostate Cancer; 2007 Jan. (Annual Meeting of the American Association for Cancer Research. Los Angeles, CA). |
| Ruparel S, Freidrichs W, Montellano R, Marciniak RA, DeGraffenried L. Regulation of Telomerase by the Akt Pathway in Prostate Cancer; 2007 Jan. (Innovative Minds in Prostate Cancer Meeting, Department of Defense, Atlanta, GA). |
| Cavazos DA, Siddiqa A, Chavez J, Marciniak RA. Inefficient Non-Homologous End Joining in Werner Syndrome Fibroblasts; 2006 Jan. (National Institutes of Health (NIH) 1st Annual Graduate Student Research Festival, Bethesda, MD). |
| Cavazos DA, Siddiqa A, Chavez J, Montellano R, Marciniak RA. Defect in Repair of Telomere Damage in Werner Syndrome Cells; 2005 Jan. (AACR 4th Annual International Conference Frontiers in Cancer Prevention Research, Baltimore, MD). |
| Ruparel S, deGraffenried L, Friedrichs W, Montellano R, Marciniak RA. Regulation of Telomerase by the Akt Pathway in Prostate Cancer; 2005 Jan. (Symposium of Cell Signaling and Cancer Therapeutics, South Padre Island, TX). |
| Siddiqa A, Chavez J, Cavazos D, Montellano R, Marciniak RA. Defect in repair of telomere damage in Werner syndrome; 2005 Jan. (Cold Spring Harbor Meeting on Telomeres and Telomerase, Cold Spring Harbor, NY). |
| Marciniak RA. ALT telomere maintenance in cancer; 2005 Jan. (Strategies for Engineered Negligible Senescence (SENS) 2, Cambridge, England). |
| Cavazos DA, Siddiqa A, Chavez J, Montellano R, Marciniak RA. Deficient Non-Homologous End Joining in Non-dividing Werner Fibroblasts; 2004 Jan. (Third Annual AACR International Conference Frontiers in Cancer Prevention Research, Phoenix, AZ). |
| Siddiqa A, Chavez JB, Monellano R, Cavazos D, Marciniak RA. Depletion of Werner protein increases the sensitivity of density arrested primary fibroblasts to stress induced premature senescence; 2004 Jan. (2nd International Conference on the Functional Genomics of Aging, Hersonissos, Crete). |
| Siddiqa A, Chavez JB, Cavazos D, Marciniak RA. Telomere repair deficiency in Werner syndrome fibroblasts; 2004 Jan. (AACR Meeting on the role of telomeres and telomerase in cancer, San Francisco, CA). |
Review Article |
| Siddiqa A, Marciniak R. Targeting the hallmarks of cancer Cancer Biol Ther 2008 May;7(5):740-741. |
| Siddiqa A, Cavazos DA, Marciniak RA. Targeting telomerase Rejuvenation Res 2006 Jan;9(3):378-390. |
Federal |
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| Funding Agency | National Institute of Health |
| Title | Oxidative stress, telomere damage and Werner Syndrome |
| Status | Active |
| Period | 4/2007 - 3/2012 |
| Role | Principal Investigator |
| Grant Detail | This grant is studying the role of telomere recombination in telomere biology. This study has been an offshoot of our studies of the role of the Werner syndrome helicase in telomere processing. |
| Funding Agency | Veterans Healthcare administration |
| Title | Oxidative stress and telomere maintenance. |
| Status | Active |
| Period | 9/2007 - 8/2011 |
| Role | Principal Investigator |
| Grant Detail | This is a study of the roles of the Werner syndrome protein in telomere maintenance. This is a continuation of studies supported by my prior Merit 1 award. |
| Funding Agency | NIH/NIA |
| Title | Training grant on the biology of aging |
| Status | Active |
| Period | 5/2003 - 9/2008 |
| Role | Contributor |
| Grant Detail | Training program for research scientists in the areas of genetics of aging, lifespan intervention analyses in animal models, and age-related diseases. Pre- and post-doctoral fellows (10 and 6 per year respectively) will be trained in the biology of aging. The trainees will participate in projects involving: programmed changes in gene expression; somatic mutations and epigenetic changes in gene expression; free radicals, DNA damage and DNA repair; aging of endocrine and immune systems; transmembrane signaling; oncogenes and tumor suppressor genes in cell growth, differentiation and apoptosis; and the molecular aspects of age-associated diseases such as Alzheimer''s disease, Parkinson''s disease and prostatic hyperplasia and neoplasia. (Dr. Austad replaced Olivia Pereira-Smith as Program Director in 2007) |
Private |
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| Funding Agency | Bristol Meyer Squibb |
| Title | A Randomized, Double-Blind, Multi-Center Phase III Study of Brivanib plus Best Supportive Care (BSC) versus Placebo plus BSC in Subjects with Advanced Hepatocellular Carcinoma (HCC) Who Have Failed or are Intolerant to Sorafenib: The BRISK PS Study |
| Status | Active |
| Period | 6/2009 - 5/2011 |
| Role | Co-Investigator |
| Grant Detail | Brivanib is a vascular endothelial growth factor receptor antagonist, which in phase I trials has shown activity in treating hepatocellular carcinoma (HCC). Sorafenib is a multi-agent tyrosine kinase inhibitor that is FDA-approved for the first-line treatment of HCC. There is no established second-line treatment of HCC after failure of sorafenib. This industry-sponsored, phase III, clinical trial is determining whether there is a role for brivanib in the second-line treatment of HCC. |
| Funding Agency | Helen Freeborn Kerr Foundation |
| Title | Targeting telomere stability for cancer treatment |
| Status | Complete |
| Period | 7/2007 - 6/2008 |
| Role | Principal Investigator |
| Grant Detail | This was a one time grant to support the purchase of additional equipment to study the possibility of using telomere destablization to specifically target cancer cells for killing. |
| Funding Agency | American Federation for Aging Research |
| Title | Oxidative Stress and Telomere Maintenance: In vitro and In vivo Studies |
| Status | Complete |
| Period | 7/2002 - 6/2007 |
| Role | Principal Investigator |
| Grant Detail | This is a career development award, given to support the research careers of outstanding clinically trained individuals who plan on a career in aging research. This project describes an analysis of the effect of oxidative stress on telomere maintenance, both in vitro in tissue culture and in vivo in knockout animals. |
State |
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| Funding Agency | University of Texas Health Science Center at San Antonio |
| Title | Mitochondrial Dysfunction in a Premature Aging Syndrome - Werner Syndrome |
| Status | Complete |
| Period | 6/2007 - 5/2008 |
| Role | Co-Investigator |
| Grant Detail | We made a novel preliminary observation - that the Werner syndrome protein is imported into mitochondria. This grant supported generating additional preliminary data demonstrating that there is mitochondrial dysfunction in the Werner syndrome cells. |