Cancer Biology Program
MISSION
Cancer Biology Program was established recently at Morehouse School of Medicine
satellite site located at the Georgia Cancer Center for Excellence at Grady under the leadership of Drs Rao and Reddy.
This program is in the early stages of development and its mission is to develop an internationally recognized program in Cancer Research at MSM so as to position
MSM at the forefront of the fight against cancer.
PROGRAM OVERVIEW
The goals of this program parallels some of the priorities established in the
National Cancer Institute’s “extraordinary Opportunities in Cancer Research”
in prevention, treatment, causes and cures of cancer.
There is significant disparity of cancer outcome for African Americans when
compared with white Americans. Our goal is to understand the molecular mechanisms behind the cancer disparities and their impact on minority populations. Understanding
the mechanism of activation of these cancers at the molecular level will give us a
clue for the increased incidence rates found in these minority groups.
Some of the cancer models that are currently being used include Breast,
Ovarian, Prostate, Ewing sarcoma, Lung, Colon, Leukemias and Lymphomas.
The goal is to develop function based diagnostic and therapeutic approaches
to human cancers.
RESEARCH PROJECTS
Dr E. Shyam P. Reddy: Professor and Co-Director, GCC Distinguished Cancer Scholar, Department of Obstetrics and Gynecology
Functional Role of ETS, fusion Onco-protieins and Tumor Suppressors in
Leukemia’s, Lymphomas and Sarcomas. Function–Based Therapeutic Approaches to Human Cancer.
Proto-oncogenes comprise a family of cellular genes that have been highly conserved throughout vertebrate evolution. These genes were initially discovered as the
normal cellular progenitor of retroviral oncogenes. Their high degree of conservation
implies that they must serve very important functions in normal growth cellular processes. The importance of cellular oncogenes (proto-oncogenes) in normal cellular
proliferation and differentiation has become well accepted. We have cloned and
characterized several proto-oncogenes, which include c-ets-1, ets-2, erg, elk-1
and human Fli-1 homologous to v-ets oncogene. Our studies demonstrate that
these ets proteins code for sequence specific transcriptional activators. Some of
these ets
genes (erg, Fli-1, ER81 and PEA3) were shown to be involved directly
in a variety
of human solid tumors (Ewing family of tumors) and also leukemias.
We have
cloned these aberrant ets-fusion transcripts present in the human solid tumors
(EWS-Fli-1, EWS-erg, EWS-ER81, EWS-ATF-1 etc) and human leukemias
(TLS/FUS-erg). Our studies indicate that these ets-fusion genes also code for
sequence specific transcriptional activators.
We have cloned and compared the functional properties of normal and aberrant fusion proteins involved in leukemias and solid tumors with t (11; 22), t (21; 22), t (16; 21),
t (7; 22) and t (12; 22) chromosome translocations (Ohno et al., 1993, Ohno et al.,
1994 and Prasad et al., 1994; Fujimura et al, 1996; Prasad et al., 1999). We have
identified the DNA binding, trans-activation and other regulatory domains of erg,
elk-1, Fli-1, EWS-Fli-1, EWS-erg, TLS-erg, EWS-ATF-1, EWS-ER81, EWS-PEA3 etc.
We have successfully targeted EWS-fusion proteins and shown that this approach can be used as a therapy for Ewing family of tumors (Ouchida et al., 1995; this work was
featured in Oncology News International, May 1995; Cancer Biotechnology Weekly,
April 1995; The Times-Picayune, March 1995). We have shown that these fusion
proteins inhibit apoptosis and are responsible for decreased ability of the tumor cells to undergo apoptosis induced by chemotherapeutic agents (Yi et al., 1997). Our results
suggest that one can use therapeutic agents which can down regulate the expression of fusion proteins in combination with chemotherapeutic agents for an effective treatment for these human solid tumors and leukemias (Yi et al., 1997). We have also cloned EWS and TLS/FUS genes involved in a variety of human diseases. We have shown that EWS and TLS/FUS codes for RNA binding proteins and localized the RNA binding domains and other regulatory domains. We have shown that protein-protein interactions of EWS-fusion proteins play an important role in transformation (Fujimura et al., 2001).
Recently, ERG gene (discovered by us) was shown to be directly involved in the
majority of Human PROSTATE CANCERS. ERG gene products were also shown
to be over expressed in these tumors (Science 310, 603, 2005). Our recent results
revealed that Erg, Fli-1 and EWS-fusion proteins target CBP- protein interactions
which are critical for transformation and apoptosis (Ramakrishnan et al., 2004).
Our results show that one can use a combination of chemotherapeutic agents along
with therapeutic agents (that target protein-protein interaction) for the effective treatment of these cancers (Ramakrishnan et al., 2004; write up on this work appeared in GCC
web site). We are at present developing novel therapeutic strategies based on the above finding. Using this strategy, we have identified novel molecular target for therapeutic intervention in Prostate and Ewing family of tumors (patent being submitted). We are
also at present developing novel proteomics based strategies to identify key interacting proteins which can be used for validation of drugs and for developing diagnostic kits for Prostate and Ewing family of tumors (Patent application submitted).
We have also cloned BRCA2 genes which are involved in human breast and ovarian
cancers and shown that BRCA2 codes for multiple isoforms and they function as tumor suppressors (Zou et al., 1999). Recently, we have shown novel enzymatic activity
associated with BRCA2, which may play an important role in tumor suppressor activity (Siddique et al., 1998; write up on this work appeared in June issue of Nature
Genetics, 1998). We have identified several key proteins that interact with BRCA2
and at present we are assessing their role in the biological function of BRCA2. We
have also cloned pTEN related cDNAs which are involved in breast, prostate and
brain tumors and at present we are studying the function of pTEN and it's related
genes. Our recent results show that they function as tumor suppressors.
Our long-term goals are (a) to study the function of ETS (Erg, Fli-1 and ETV1/ER81,
PEA3), BRCA2 , PTEN and fusion onco-proteins and also study their role in Ewing’s
sarcoma, human Prostate, Ovarian and Breast Cancers (b) to develop function based diagnostic and therapeutic approaches to human cancer and (c) to study how these genes are linked to cancer disparity seen in African American and Hispanic subgroup.
Dr M. Veena N. Rao: Professor and Co-Director, GCC Distinguished Cancer Scholar, Department of Obstetrics and Gynecology
Molecular and Functional Dissection of ELK-1 and BRCA1 Tumor Suppressor
Genes: Role in Cell Growth, Differentiation, Signal Transduction, Apoptosis of Breast, Ovarian and Prostate Cancers.
One of the ongoing projects in my lab is centered on the ETS super family of genes
(ETS-1, ETS-2, ERG, TEL, PEA3, Fli-1, Elk-1, SAP1, etc.) which we have identified,
cloned, characterized their functions and studied their role in leukemias, lymphomas,
and sarcomas. The ets gene family encodes a family of nuclear localized,
sequence specific DNA binding transcriptional factors which are involved in leukemia’s, lymphomas and sarcomas. Deregulation and mutations of ETS proteins are
predominantly found in human cancers. We have identified a new member of the
ETS family and named it Elk-1 (ETS-like gene). We have mapped Elk-1 on a region of chromosome X that is frequently altered in several human diseases. Elk-1 was found
to bind to DNA and function as a transcriptional activator. Elk-1 forms a SRF dependent ternary complex with SRE similar to p62TCF. Ternary complex factors play a vital role
in the activation of immediate-early genes such as c-Fos, EGR in response to a series of mitogenic and stress stimuli. Elk-1 mediates signaling by three types of MAPKS:
ERK, JNK and p38. The defective functioning of this signaling network is the root
cause of widespread diseases such as cancer. Breast cancers have a decreased ability to undergo cell death. We have found the Elk-1 gene product to induce apoptosis of human breast cancer cells. Recently activation of AKT has been implicated as one of the mechanisms involved in breast cancer survival and drug resistance. Interestingly AKT was found to inhibit the expression of ELK-1.We plan to study the role of AKT/ELK-1 in drug resistance.
The second project in my lab focuses on the BRCA1 gene products.BRCA1 gene
was shown to be either lost or mutated in families with breast, ovarian and prostate
cancer. Among sporadic cases of breast cancer, expression of BRCA1 is reduced or undetectable in high grade ductal carcinomas suggesting the involvement of this
gene in the etiology of breast cancers.BRCA1 is a multifunctional protein that
interacts with multiple proteins suggesting that these functions are manifested
through its association with these proteins. Several BRCA1 splice variants are found in different tissues but their regulation and possible functions are poorly understood at the moment. The presence of these BRCA1 variants can create confusion to genetic
counseling because no advice can be given to patients regarding whether they are responsible for developing Breast cancer. Therefore elucidating the functions of these splice variants would help in understanding the role of this tumor suppressor in Breast and Ovarian cancer. We have cloned and characterized two new BRCA1 splice variants BRCA1a and BRCA1b which are expressed in normal breast tissues as well as both in non-malignant and tumor-derived breast cancer cells.
In fact we have recently obtained patent for the Splice variants of BRCA1 Using antisense BRCA1a RNA we have inhibited the endogenous BRCA1 in mouse cells and shown that mere down regulation of expression of BRCA1 is sufficient to achieve transformation. Introduction of BRCA1a into human Breast cancer cells resulted in apoptosis of these cells. Furthermore, we have found ELK-1 to be a potential downstream target of BRCA1 proteins. Both these splice variants inhibited the growth as well as Fos promoter activity. Based on these results we plan to develop single cell-based assays for detecting functionally relevant changes in patients with BRCA1 mutations. Once the functions of BRCA1 have been determined, therapeutic strategies will be developed to correct cells that have lost functional BRCA1. Treatments that are aimed at increasing the apoptotic or tumor suppressor threshold by BRCA1 gene therapy may have the potential to prevent the progression of these cancers. Therefore our efforts will be directed towards BRCA1 gene therapy in Breast, Ovarian and Prostate cancers. This work will also help in defining the tumor suppressor defect that is conferred by clinical BRCA1 mutations in these cancers. Alternately, we also plan to use therapeutic agents that can activate or repress BRCA1 downstream signals involved in apoptosis for the treatment of these cancers.
Results from this work will lead to improved knowledge of the functional significance of these splice variants which can be of great benefit to the patients who carry them. Future efforts will be focused on reducing the cancer disparities among minority populations using proteomics based sophisticated nano technologies.
ADDITIONAL RESEARCH
Dr Yasuo Fujimura: Research Instructor, Department of Obstetrics and Gynecology
Development of Proteomics based Therapeutic Approaches to Human Cancers.
Felix Aikhionbare: Research Assistant Professor, Department of Medicine
The Identification of Genetic changes in Mitochondrial Genome associated with tumor genesis, and evaluation of their significance
Gary Sanford: Professor, Department of Microbiology, Biochemistry and Immunology,
Modulation of lung growth, maturation, and function, remoldeling of the pulmonary vasculature; cellular and molecular studies of the role of a soluble lectins in these processes.
Ward Kirlin: Associate Professor, Department of Pharmacology and Toxicology
Chemical carcinogenesis and toxicology; molecular regulation of induction pathways involved in activation and detoxification of carcinogens.
Kamla Dutt: Professor, Department of Pathology
Retinal cell biology, cell commitment, differentiation, tissue engineering, human retinal cells.
Julian Menter: Research Professor, Department of Medicine
Photochemistry and photobiology of skin cancer and skin aging; photoprotection by fabric materials.
ADDITIONAL RESEARCH PARTICIPANTS
Roland Matthews: Chair/Associate Professor, GCC Distinguished Cancer Scholar, Department of Obstetrics and Gynecology
Yap, Oi Wah Stephanie: Assistant Professor, Department of Obstetrics and Gynecology
Winston Thompson: Research Associate Professor, Department of Obstetrics and Gynecology
Xuebiao Yao: Associate Professor, GCC Distinguished Cancer Scholar, Department of Physiology
Joel Okoli: Assistant Professor, Department of Surgery,
Harvey Bumpers: Associate Professor, Department of Surgery
Ganapathy Bhat: Research Instructor, Department of Obstetrics and Gynecology
Moshood Olatinwo: Assistant Professor, Assistant Residency Program Director, Department of Obstetrics and Gynecology
Eric Flenaugh: Assistant Professor, Department of Medicine