Molecular Diagnostics & Therapeutics
Cancer Therapeutics Laboratory
The molecular basis of brain, breast and pancreatic cancers and its implications for patients.
Summary: We are interested in identifying and characterizing the genes that cause cancer and drug resistance and the application of this knowledge to the management of patients.
Research in our laboratory is focused on several areas:
1. Identify the genes that cause drug resistance.
2. Identify drugs that reduce resistance and enhance the chemotherapeutic drug effect without causing unwanted side effects.
3. Identify combination therapy to personalize medicine to different patient groups.
4. Investigate how cancer cells within a primary tumor acquire the ability to invade and metastasize.
5. Identify drugs that inhibit tumor invasion and metastasis.
6. Studies on angiogenesis and drugs that inhibit tumor angiogenesis.
Our major focus is on cancers of the brain, breast and pancreas. The goal of our research is to develop new approaches to prevent or treat cancers through a better understanding of the genes and pathways underlying their pathogenesis.
Novel therapeutic agents that target the specific defects in cancer are under development.
We developed an interest in chemotherapy-induced DNA damage and its repair, which remains the current main focus of our lab. The anticancer drug resistance focusing on the unique DNA repair protein MGMT (O6-methylguanine DNA methyltransferase) has been funded recently by Florida Department of Health. Ongoing research projects are focusing on biochemical mechanisms of anticancer drug resistance and their modulation for improved therapies, DNA repair, post-translational modifications, cell cycle checkpoints and p53 tumor suppressor, chemoprevention and exploiting the posttranslational regulation of MGMT for enhanced anticancer therapies.
Anti-estrogens, particularly tamoxifen, have proven to be effective in the treatment of breast cancer. Resistance to tamoxifen, however, is a serious obstacle in the management of breast cancer. About 40% of ER-positive tumors fail to initially respond to tamoxifen therapy, and of those breast tumors initially responding to tamoxifen many have eventually develop resistance. Thus, a better understanding of the mechanism of anti-estrogen resistance could guide and promote new therapeutic strategies for breast cancer treatment. Our laboratory is also interested in the elucidation of factors involved in resistance to anti-estrogen therapy to breast cancer patients. The primary objective of our research study is to investigate the mechanism of anti-estrogen drug resistance most often developed in breast cancer patients and ultimately modulate the resistance by developing new therapeutic strategies. The overall aim of our research is to establish a role for O6-methylguanine DNA methyl transferase (MGMT) expression in tamoxifen resistance and to explore the development of MGMT inhibitors as therapeutic options in tamoxifen-resistant breast cancer. In the end, we hope to provide novel therapeutic strategies, which will avoid and overcome drug-related resistance and most importantly, prolong the lives of breast cancer patients.
C. Bobustuc, Cheryl H. Baker, Arati Limaye, Wayne D. Jenkins, Nicholas
G. Avgeropoulos and Santhi D. Konduri. Levetiracetam Enhances
p53-Mediated MGMT Inhibition and Sensitizes Glioblastoma Cells to
Temozolomide Neuro-Oncology (Accepted).
2. Santhi. D. Konduri, Jonathan Ticku, George. C. Bobustuc, Robert
M. Sutphin, Jimmie Colon, Kishor K. Bhakat, Srivenugopal K. Kalkunte,
Cheryl H. Baker. Blockade of MGMT Expression by O6 Benzyl Guanine Leads
to Inhibition of Pancreatic Cancer Growth and Induction of Apoptosis.
Clin Cancer Res 2009;15 6087-6095.
3. Abdelrahim, M., Santhi D. Konduri, Basha, M.R., Abudayyeh, A., and
Baker, C.H. Angiogenesis: a recent update and potential drug approaches.
2009. Int J Oncol. 2010 Jan;36(1):5-18.
4. Colon, J., Basha, M.R., Madero-Visbal, R, Santhi D Konduri, Baker,
C.H., Herrera, L., Safe, S., Sheikh-Hamad, D., Abudayyeh, A, Alvarado,
B. and Abdelrahim, M. Tolfenamic acid inhibits lung cancer cells and
tumor growth by repressing specificity proteins and c-Met. 2009. Invest
New Drugs. 2009 Oct 23. [Epub ahead of print].
5. Santhi D Konduri, Jimmie Colon, Cheryl Baker and Maen Abdelrahim.
Tolfenamic acid inhibits survivin gene expression and sensitizes
pancreatic tumor cells to radiation therapy. Mol Cancer Ther 2009; 8(3)
6. Benny Abraham Kaipparettu, Simeen Zubairy, Santhi D. Konduri,
Wenshen Liu, Matjaz Rokavec, Heiko van der Kuip, Reiner Hoppe, Peter
Fritz, Werner Schroth, Ina Merz, Gokul M. Das, Steffi Oesterreich,
Hiltrud Brauch. Estrogen-mediated down-regulation of CD24 in breast
cancer cells. Int J Cancer. 2008 Jul 1;123(1):66-72.
7. Aejaz Sayeed, Santhi D. Konduri, Wensheng Liu, Sanjay Bansal,
Fengzhi Li, and Gokul M. Das. Inhibition by of transcriptional
repression by p53: a mechanism for anti-apoptotic function of ERa Cancer
Research 2007; 67: 7746-7755.
8. Wensheng Liu, Santhi D. Konduri, Sanjay Bansal, Bijay M. Nayak,
Sigrid a. Rajasekaran, Pratima Srivastava, Sankunny M. Karuppayil,
Ayyappan K. Rajasekaran and Gokul M. Das. Repression of p53 function by
direct interaction with oestrogen receptor a. (Equal contribution). J
Biol Chem. 2006 Apr 14;281(15):9837-40. (Equal Contribution)
9. Santhi D. Konduri, Srivenugopal S Kalkunti, Niranjan Yanamandra,
Francis Ali-Osman, Dzung H Dinh, William C Olivero, Meena Gujrai, and
Jasti S Rao. Tissue Factor Pathway Inhibitor-2 (TFPI-2) CpG island
hyper-methylation is responsible for the down regulation of TFPI-2
expression in human glioma cells. Oncogene 2003; 22,4509-4516.
10. Niranjan Yanamandra, Mark A. Berhow, Santhi D. Konduri, Dzung H.
Dinh, William c. Olivero, Garth L. Nicolson and Jasti S. Rao.
Triterpenoids from Glycine max decrease invasiveness and induce
caspase-mediated cell death in human SNB19 glioma cells. Clinical &
Experimental Metastasis 2003; 20: 375-383.
11. Santhi D. Konduri, Niranjan Yanamandra, Dzung H Dinh, William H
Olivero, Meena Gujrati, Donald C. Foster, Walter Kisiel and Jasti S Rao.
Physiological and Chemical inducers of Tissue Factor Pathway
Inhibitor-2 in Human Glioma Cells. Int. J Oncology. 2003
12. Santhi D. Konduri, Yanamandra N, Siddique K, Joseph A, Dinh DH,
Olivero WC, Gujarati M, Kouraklis G, Swaroop A, Kyritsis AP, Rao JS.
Modulation of cystatin C expression impairs the invasive and tumorigenic
potential of human glioblastoma cells. Oncogene. 2002 Dec
13. Santhi D. Konduri, Osman FA, Rao CN, Srinivas H, Yanamandra N,
Tasiou A, Dinh DH, Olivero WC, Gujrati M, Foster DC, Kisiel W, Kouraklis
G, Rao JS. Minimal and inducible regulation of Tissue Factor Pathway
Inhibitor-2 (TFPI-2) in Human Gliomas. Oncogene 2002 Jan
14. Santhi D. Konduri, Rao CN, Nirmala C, Anastasia T, Mohanam, S, Kin
Y, Sajani SK, Fuller GN, Francis AO and Rao JS. A novel function of
tissue factor pathway inhibitor-2 (TFPI-2) in Human Glioma invasion.
Oncogene, 2001, 18; 20 (47): 6938-45.
15. Santhi D. Konduri, A. Tasiou, N. Chandrasekar and J.S. Rao. Over
expression of tissue factor pathway inhibitor-2 (TFPI-2) decreases the
invasiveness of prostate cancer cells in vitro. Int. J Oncology. 2001,
16. Santhi D. Konduri, Sajani S Lakka, Anastasia Tasiou, Niranjan
Yanamandra, Christopher S Gondi, Dzung H. Dinh, William C. Olivero,
Meena Gujrati and Jasti S. Rao. Elevated levels of cathepsin B in human
glioblastoma cell lines. Int J Oncol. 2001; 19 (3): 519-24.
17. Anastasia T, Santhi D. Konduri and Rao JS. A novel role of tissue
factor pathway inhibitor-2 (TFPI-2) in apoptosis of malignant human
gliomas. Int J Oncol. 2001; 19(3): 591-7.
18. Santhi D. Konduri, Anastasis Tasiou, Nirmala Chandrasekar, Garth
L. Nicolson and J.S. Rao. Role of tissue factor pathway inhibitor-2
(TFPI-2) in amelanotic melanoma (C-32) invasion. Clin.Exp.Metastasis,
2000; 18: 303-308.
19. S.S. Lakka, Santhi D. Konduri, S. Mohanam, G.L. Nicolson and J.S.
Rao. In vitro modulation of human lung cancer cell line invasiveness by
antisense cDNA of tissue pathway inhibitor-2. Clin Exp Metastasis, 2000;
20. Niranjan Yanamandra, Santhi D Konduri, Mohanam Sanjeeva and Jasti S
Rao. Down regulation of Urokinase-type plasminogen activator receptor
(uPAR) Induces caspase mediated cell death in human glioblastoma cell
line. Clin Exp Metastasis. 2000; 18 (7): 611-615.
21. Rao, C.N., Sajani S. Lakka, Kin, Y., Santhi D. Konduri, Fuller,
G., Mohanam, S. and J.S. Rao. Expression of tissue factor pathway
inhibitor-2/matrix-associated serine protease inhibitor inversely
correlates with grade of malignancy in human glioma. Clin Cancer Res
2001; 7: 570-576.
22. Chandrasekar Nirmala, Sushma L Jasti, Raymond Sawaya, Anthanassios
P. Kyritsis, Santhi D. Konduri, Francis Ali-Osman, Jasti S. Rao and
Sanjeeva Mohanam. Effects of radiation on the levels of MMP-2, MMP-9,
and TIMP-1 during morphogenic glial-endothelial cell interactions. Int.
J. Cancer, 2000; 88: 766-771.
23. Santhi D Konduri, A. Radha Rama Devi and Paturu Kondaiah.
Amplification of phenylalanine hydroxylase and cystathionine beta
synthase transcripts in human peripheral lymphocytes by RT-PCR.
Biochemistry & Molecular Biology International. 1998; 45 (4):
24. Kondaiah, P and Santhi D Konduri. PCR applications in the prenatal
diagnosis of single gene disorders. In "A Handbook of Prenatal
Diagnosis and Reproductive Genetics". Edited by Dr. Kamini A. Rao under
the egis of the Federation of Obstetric and Gynaecological Societies of
India. 1997; 89-98.
25. Santhi D Konduri, P. Veerraju and B.S. Sridhara Rama Rao.
Screening for mucopolysaccharidoses among mentally retarded children. J.
Hum. Ecol. 1997; 8: 73 - 74.
26. Santhi D Konduri, P. Veerraju and B.S. Sridhara Rama Rao. Two
cases of Homocystinuria from Coastal Andhra Pradesh. Journal of Human
Ecology. 1997; 9: 195-196.
27. Santhi D Konduri, P.Veerraju and B.S. Sridhara Rama Rao. Alkaptonuria – A case Report. J. Hum. Genet. 1995; 1:41-45.
28. Santhi D Konduri, P. Veerraju and B.S Sridhara Rama Rao. Report of
three cases of Mucopolysaccharidoses and an unusual case of
hyperaminoaciduria detected during the screening of mentally retarded
children. Human Heredity. 1994; 44: 90-94.
29. Santhi D Konduri, P. Veerraju and B.S. Sridhara Rama Rao. An
unusual case of Hyperaminoaciduria. Medical and Nutritional Research
30. Santhi D Konduri, P. Veerraju and B.S. Sridhara Rama Rao.
Sanfilippo Syndrome. A case study. Ind. J. Pediatr. 1993; 60: 595-597.
31. Santhi D Konduri, P. Veerraju and B.S. Sridhara Rama Rao. Two
cases of Hunters syndrome from Coastal Andhra Pradesh. Medical and
Nutritional Research Communications. 1993; 1: 73-75.
P and Santhi D Konduri. PCR applications in the prenatal diagnosis of
single gene disorders. In “A Handbook of Prenatal Diagnosis and
Reproductive Genetics”. Edited by Dr. Kamini A. Rao under the egis of
the Federation of Obstetric and Gynaecological Societies of India. 1997;