Perelman School of Medicine at the University of Pennsylvania

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The Department of Radiation Oncology is in the new Perelman Center. Occupying approximately 80,000 square feet on the Concourse Level, the new treatment facilities includes the most advanced proton and conventional radiation treatment modalities available as well as public spaces designed for the highest levels of patient comfort.


Maity Lab

Amit Maity, M.D. , Ph.D.
Professor
  Amit Maity
University of Pennsylvania School of Medicine 
Department of Radiation Oncology
2 PCAM West 
3400 Civic Center Blvd 
Philadelphia, PA 19104
Office: (215) 662-2712 
Lab: (215) 573-3353 
Fax: (215)-898-0090
maity@uphs.upenn.edu

 

Lab Members:
George Cerniglia, Ph.D.   (Research Specialist)
 
Publications

Research Interests

1)      Regulation of VEGF/HIF-1a by the PI3K/Akt pathway

         Vascular endothelial growth factor (VEGF) is an important regulator of blood vessel growth in cancer, and targeting it may be a means of inhibiting tumor growth. We have focused on a specific pathway that is often deregulated in human cancers, the PI3 kinase/Akt pathway.  We have found that activation of this pathway leads to increased VEGF expression and have made significant progress in the last year in understanding the mechanism underlying this.  Our data indicate that Akt activation is associated with phosphorylation of a transcription factor Sp1, resulting in increased binding to the VEGF promoter and activation of VEGF mRNA transcription.  This pathway is operative under normal oxygen conditions; however, the PI3K/Akt pathway also appears to contribute to increased VEGF expression under hypoxia by increasing expression of a different transcription factor, hypoxia-inducible factor (HIF)-1alpha.  Mechanistically this occurs through increased translation of the protein.  Therefore, we have identified two separate mechanisms by which Akt can increase VEGF expression and continue to try to understand the details of these pathways.

         The studies mentioned above provide insight into how oncogenic changes lead to deregulated tumor growth; however, we have also been conducting studies that may have great relevance to clinical radiotherapy.  A number of EGFR inhibitors are currently being tested in the clinic, sometimes in combination with radiotherapy. These inhibitors can also decrease the expression of VEGF, and our studies show that the PI3K/Akt pathway is involved through both the Sp1 and HIF-1a transcription factors described above.  Furthermore, we have found that one of these inhibitors, gefitinib, appears to increase tumor oxygenation in vivo.  In theory increased tumor oxygenation should improve the efficacy of radiotherapy since optimal DNA damage and cell killing by radiation requires the presence of oxygen. It is possible that this effect on increasing tumor oxygenation results from decreased VEGF expression.  This finding could be of great practical importance in terms of combining EGFR inhibitors with radiation, and we are vigorously pursuing this particular avenue of investigation.

2)      Modulation of radiosensitivity by agents that alter signal transduction

         There is evidence that activation of the PI3K/Akt pathway leads to increased resistance to radiation therapy. We have been conducting experiments with Dr. Anjali Gupta, another PI in the department, with nelfinavir, an HIV protease inhibitor that sensitizes tumors to radiation, perhaps by inhibiting the PI3K/Akt pathway. We have found that the drug can increase tumor oxygenation, which has important implications in the use of the drug with radiotherapy since increased oxygenation of hypoxic tumors should make them more sensitive to radiation. We are very interested in determining how nelfinavir works to radiosensitize tumors in vivo.  We are also investigating other PI3K inhibitors that are currently undergoing clinical testing to determine their effects on radiosensitivity. 

3)      Clinical detection of hypoxia in patients with cancer

         Many human cancers contain regions of hypoxia.  Hypoxia is associated with resistance to radiation and perhaps to certain chemotherapeutic agents as well.  Drs. Cameron Koch and Sydney Evans in our department have developed an agent (EF5) that can be used to detect these hypoxic regions.  However, this agent is difficult to use in that the patient must be injected with EF5, then the tumor must be removed within 24-48 hours and stained for EF5. A less invasive means is be to inject [F-18] EF5 into a patient and then use PET scanning to detect EF5 binding.  We have been involved in the development of protocols that use [F-18] EF5 PET scanning in patients.  A protocol is currently open for patients with brain tumors, and we are developing one that will be used in patients with lung cancer. Ultimately we plan to incorporate this [F-18] EF5 PET scanning to determine whether tumor oxygenation is altered by various biological modifiers and radiation.

Education

INSTITUTION
DEGREE
YEARS
FIELD OF STUDY

Boston University Boston, MA

BA

1979-1985

Mathematics

Boston University School of Medicine, Boston Medicine, MA   (Combined BA/MD Degree Program)

MD

1981-1985

Medicine

University of Pennsylvania

PhD    

1992-1995

Pathology

Postgraduate training and fellowship appointments

1985-1988

Residency, Internal Medicine, Mount Sinai Hospital, New York, NY

1988-1991      

Residency, Radiation Oncology, Hospital of the University of Pennsylvania           Philadelphia, PA

1991-1995      

Postdoctoral trainee, Department of Radiation Oncology
University of Pennsylvania, Philadelphia, PA

1995-1997

Postdoctoral researcher, Department of Medicine

Faculty appointments

1992-1995      

Instructor of Radiation Oncology 
University of Pennsylvania School of Medicine

1997-2006

Assistant Professor of Radiation Oncology 
University of Pennsylvania School of Medicine

2006-present

Associate Professor of Radiation Oncology 
University of Pennsylvania School of Medicine

Awards, honors, memberships in honorary societies

1984

Alpha Omega Alpha, Boston University School of Medicine

1985

Phi Beta Kappa, Boston University

1991-93

American Society for Therapeutic Radiology and Oncology  (ASTRO) Research Fellowship

1995

Student Travel Award 
43rd Annual Meeting of the Radiation Research Society, San Jose, CA

1995

Travel Award 
10th International Congress of Radiation Research, Wurzburg, German

1995

Saul Winegrad, M.D. Prize for Outstanding Ph.D. Thesis, 
University of Pennsylvania

2005

Senior Investigator Travel Award, 47th Annual ASTRO Meeting, Denver, CO

Memberships in Professional and Scientific Societies

National Societies:

American Society for Therapeutic Radiology and Oncology (ASTRO)

 

Abstract Reviewer for ASTRO Annual Meeting (2005, 2006)

 

Member of ASTRO Education Committee (2006)

American Association for the Advancement of Science

American Association for Cancer Research (AACR)

 

Reviewer for Post-doctoral Fellowship Awards (2006)

Radiation Research Society

Society for Neuro-oncology (SNO)

 

Abstract reviewer for SNO Annual meeting (2003)

 
 
National Scientific Committees

American Heart Association Cellular and Molecular Biology Study section

 

ad hoc member, (April 2003)

NIH Study Section (April 2004)

 

ad hoc member, Therapeutic Target Development Cluster P01 review panel

NIH Study Section (May 2005)

 

ad hoc member, Experimental Therapeutics Cluster P01 review panel

NIH Study Section (February 2006)

 

ad hoc member, Experimental Therapeutics Cluster P01 review panel

NIH Rapid Access to Intervention Development (RAID) review section (May 2006)

NIH Study Section, Radiation Therapy and Biology (RTB) (October, 2006)

 

ad hoc member

 

Selected Bibliography (since 2000)

Research publications, peer reviewed (of 34):

Maity, A, Solomon, D. Increased stability and transcription both contribute to the induction of the urokinase plasminogen activator receptor (uPAR) message by hypoxia. Exp. Cell. Res. 255: 250-257, 2000.

Maity, A, Pore, N, Lee, J, Solomon, D, O’Rourke, D. EGFR regulates VEGF transcriptional activation in human glioblastoma cells by a hypoxia-independent pathway involving Ras and PI(3) kinase. Cancer Res.  60: 5879-5886, 2000.

Maity A, Sall W, Koch C J, Evans, SM. Estrogen-resistant MCF-7-5C breast carcinoma cells display greater hypoxia in vivo than estrogen-sensitive MCF-7 cells in spite of comparable induction of VEGF to b-estradiol and hypoxia Breast Cancer Research and Treatment 67: 51, 2001. 

Chen, C, Pore, N, Behrooz, A, Ismail-Beigi, F and Maity, A.  Regulation of Glut1 by HIF1: Interaction between H-ras and hypoxia.  J. Biol. Chem. 276: 9519, 2001.

Ziemer, LS, Koch, CJ, Maity, A, Magerelli, DP, Horan, AM, Evans, SM Hypoxia and VEGF mRNA expression in human tumors. Neoplasia 3:500-8, 2001.

Pore, N, Liu, S, Haas-Kogan, D A, O'Rourke, D M, Maity, A PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Res. 63: 236, 2003. 

Chen, C, Shu, H-K G, Goldwein, JW, Womer, RB, Maity, A Volumetric  considerations in radiotherapy for pediatric parameningeal rhabdomyosarcomas. Int. J. Radiat. Oncol. Biol. Phys. 55:1294-9, 2003.

Maity, A, Shu, H-K G, Janss, A, Belasco, JB, Rorke, R, Phillips, PC, Sutton, LN, Goldwein, J.W. Craniospinal radiation in the treatment of biopsy-proven intracranial germinomas: twenty-five years experience in a single center Int. J. Radiat. Oncol. Biol. Phys. 58:1165-1170, 2004.

Stripp, DCH, Maity, A, Janss, AJ, Belasco, JB, Tochner, ZA, Goldwein, JW, Moshang, T, Rorke, LB, Phillips, PC, Sutton, LN, Shu, H-KG: Surgery with or without radiation therapy in the management of craniopharyngiomas in children and young adults.  Int. J. Radiat. Oncol. Biol. Phys. 58: 714-720, 2004.

Bucci, MK, Maity, A, Janss, AJ, Belasco, JB, Fisher, MJ, Tochner, ZA, Rorke, L, Sutton, LN, Phillips PC and Shu, H-KG:  Near complete surgical resection predicts a favorable outcome in pediatric non-brainstem, malignant gliomas: results from a single center in the MRI era. Cancer 101: 817-824, 2004. 

Maity, A, Shu, H-K, G, Judkins, AR, Fisher, MJ, Dwyer-Joyce, LEA, Vaughn,DJ. Testicular seminoma sixteen years after treatment for CNS germinoma.  J. Neuro-oncol. 70: 83-85, 2004.

Maity, A, Shu, H-K, G, Tan, J E, Ruffer, J, Sutton, LN, Tochner, Z, Lustig, R Treatment of pediatric intracranial arteriovenous malformations with linear accelerator based-stereotactic radiosurgery: the University of Pennsylvania experience. Pediatr Neurosurg 40: 207-14, 2004. 

 Pore, N, Liu, S, Shu, H-S, Li, B, Haas-Kogan, D, Stokoe, D, Milanini-Mongiat, J, Pages G, O’Rourke,, DM, Bernhard, E, Maity, A  Akt activation can upregulate VEGF expression independently of hypoxia inducible factor-1 via phosphorylation of Sp1 family members. Mol. Biol. Cell. 15: 4841, 2004. 

Shi, Y, Lee, CS, Wu, J, Koch, CJ, Thom, SR, Maity, A, Bernhard, E.  The effects of  hyperbaric oxygen exposure on experimental head and neck tumor growth, oxygenation and vasculature, Head and Neck 27: 362, 2005. 

Liu, F, Pore, N, Kim, M, Voong, R, Dowling, M, Maity, A, Kao, G, Sp transcription factors drive expression of human histone deacetylase 4 through its promoter. Mol. Biol. Cell. 15: 4841, 2005.

Tsai, JH, Makonnen, S, Feldman, M, Sehgal, CM, Maity, A, Lee WM. Ionizing radiation inhibits neovascularization by inducing ineffective angiogenesis. Cancer Biol. Ther. 4: 1395, 2005.

Weiner, DJ, Maity A, Carlson, CA, Ginsberg, JP. Pulmonary function abnormalities in children treated with whole lung irradiation. Pediatr Blood Cancer 46: 222, 2006

Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A. EGFR tyrosine kinase inhibitors decrease vascular endothelial growth factor (VEGF) expression by both hypoxia inducible factor (HIF)-1 independent and dependent mechanisms. Cancer Res. 66: 3197, 2006.

Pore N, Jiang Z, Shu, H-K, Bernhard, E, Kao GD, Maity A. Akt activation can augment HIF-1a expression by increasing protein translation through an mTOR-independent pathway. Mol. Cancer Res. 4: 471, 2006.

Pore, N, Gupta, AK, Cerniglia, GJ, Jiang, Z, Bernhard, EJ, Evans SM, Koch CJ, Hahn SM, Maity A. Nelfinavir downregulates HIF-1a and VEGF expression and increases tumor oxygenation: implications for radiotherapy. Cancer Res. (in press September 2006)

Pore, N, Gupta, AK, Cerniglia, GJ, Maity, A.  HIV protease inhibitors decrease HIF-1a and VEGF expression and angiogenesis in glioblastoma cells. Neoplasia (in press)

Editorials, Reviews, including participation in committee reports (out of 10):

Maity, A, Pruitt, AA, Judy, KD, Phillips, P C “Cancer of the Central Nervous System” in Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG (ed.)  Clinical Oncology, Lippincott, Philadelphia, 2004.

Maity, A. and Tuttle, S.W. 2-deoxyglucose and radiosensitization. Teaching an old DOG new tricks?  Cancer Biol Ther 11:5,2006

Shu, H-K, Maity, A, Tochner, Z “Treatment Modalities: Radiation Therapy” in Brodeur, G, Manno, C.S. (ed.) Requisites in Pediatrics: Pediatric Hematology/ Oncology, Mosby, St. Louis (in press; February 2007)

Maity, A, “Radiation Therapy for Sarcomas” in J Khurana (ed.) Skeletal Pathology, (2nd ed.) (in press)

Ginsberg, J, Maity, A, “Testicular late effects“ in CL Schwartz, LS Constine, WLHobbie, KS Ruccione  (ed.) Survivors of Childhood Cancer Assessment and Management, (2nd ed.) (in press)

Research Support

ACTIVE
 

RO1-CA-093638-01

PI: Maity

15% effort

 

July 2006 €“ May 2011

“Regulation of VEGF/HIF-1 by AKT: Implications for Radiotherapy”

We will study how the expression of VEGF, an important mediator of blood vessel growth, is increased in human tumors.  The clinical importance of these studies is that EGFR inhibitors currently being used in the clinic may work though these pathways to increase the oxygenation of tumors.  Increased oxygenation should make tumors more sensitive to radiation; therefore, our studies may be important in helping to optimize the combination of EGFR inhibitors with radiation. 

 
 
COMPLETED
 

P50-AT00428-01

P.I.: Thom

 NIH SCOR    

 

14% effort; project 2

September 2000 - July2005

 “Specialized Center of Research in Hyperbaric Oxygen Therapy”

“Specialized Center of Research in Hyperbaric Oxygen Therapy”

The research theme of this proposal is to examine the mechanisms, action, safety, and clinical efficacy of hyperbaric oxygen therapy relative to the treatment of head and neck cancer. The hypothesis is that hyperbaric oxygen therapy will benefit patients undergoing reconstructive surgery after radiation therapy because, at pharmacologic doses, oxygen augments angiogenesis and impedes specific types of intercellular adherence.

 Role: co-investigator, project 2

 
 

RO1-CA-093638-01

PI: Maity

 NIH NCI

 

 20% effort

 

July 2002 €“ June 2006

 

“Regulation of VEGF in tumors by Ras EGF and PTEN”

The goal is to gain a clearer understanding of the mechanism of VEGF overexpression in cancers under normoxia. This will also lead to a better understanding of HIF-1 regulation and of the effects of EGFR activation and Ras and PTEN mutations on gene expression.




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