The Use of the Nef Apoptotic Peptides as a Potential Therapy to Fight Cancer

Faculty involved:

Description:
Breast Cancer is one of the most common malignancies affecting women in the western world today. The lifetime risk of getting breast cancer is approximately 10%. For the most part, deaths from breast cancer as well as other cancers are due to the physiologic consequences of the growth of metastatic tumors, rather than the effects of the primary tumor. Patients whose primary tumors are detected before metastatic cells have been seeded to distant sites can be generally cured. Thus, two major problems in cancer treatment are: (i) determining whether the tumor has indeed seeded metastatic cells, and (ii) how to treat patients in which the metastatic process has begun.

The unique chemokine receptor/chemokine ligand pair, CXCR4/SDF-1a, has been implicated in breast carcinoma development ({3408}). CXCR4 has been shown to be highly expressed by human breast carcinoma cells, although the primary or normal mammary epithelial cell types do not express the CXCR4 receptor. Expression of this chemokine receptor on the cell surface appears to promote metastasis by acting directly on breast tumor cell migration and invasion.

Our previous in vitro work with the HIV-1 apoptotic Nef peptide shows that this molecule has an apoptotic effect on a number of cell lines containing CXCR4 including carcinoma cell lines ({5060}, {5298}, preliminary results). Further, this apoptotic effect does not manifest itself on normal mammary epithelium (preliminary results). Finally, we have preliminary data in a mouse metastatic model developed by Dr Harvey Bumpers that suggests Nef apoptotic motif does preferentially slow metastasis from a primary tumor formed from the MDA-MB-231 cell line (preliminary results), and the effect is driven through the CXCR4 receptor agreeing with our previous results.

A funded collaboration between Drs Bond and Dr Harvey Bumpers, a clinical oncologist in the Department of Surgery, has developed looking to see if CXCR4 expression on tumor cells is a potential target for the Nef apoptotic peptide. If this is correct, the Nef apoptotic peptides could be used as a breast cancer therapeutic. A full patent related to these findings has been filed.

Our Relevant Publications:
5322. Bumpers et al., 2005

Other Relevant Publications:
3408. Muller et al., 2001

Patent:
"Tumor Cytotoxicity Induced by Modulators of the CXCR4 Receptor". Filed 3/20/02. USSN 10/392,324. This invention relates to the use of HIV-1-, HIV-2-, SIV- or FIV- associated gp120 molecules as therapeutic agents against epithelial carcinomas.

Characterization of a Traditional African Treatment for AIDS

Faculty involved:

Description:
Traditional healers in the Senegal region of Africa have used mixtures of local medicinal plants as a treatment for AIDS since the beginnings of the epidemic. However, little has been done to determine if these traditional treatments have a demonstrable scientific basis. We are currently testing one such treatment to determine if the medicinal plants have antiviral properties. Our initial findings suggest that extracts of these plants have antiviral properties and could represent an interesting lead toward the development of new anti-retroviral treatments.

Proteomic Characterization of Gag p6 On Interactions With Other Cellular Proteins.

Faculty involved:

Description:
It is known that HIV-1 Gag protein is a major determinant of virus assembly. It has also been shown that Gag serves a source of interaction of the virus with host proteins, for example, human cyclophilin A and TSG101. This is a collaboration between an established researcher in the field of assembly and our proteomics core facility, which is directed by an MBI faculty member. The collaboration has been the impetus for identifying several new protein interactions, one of which is the source of a manuscript currently under review for publication in PNAS.

Determination of Whether Soluble Factors are Secreted by Chlamydia-Infected Cells that Promote HIV-1 Replication

Faculty involved:

Description:
STDs are known to be co-factors in infection by HIV. In many cases the STD provides an entry point for the virus to cross the mucosa. Infection with Chlamydia does not typically provide such a barrier breach but does promote infection. We are testing a hypothesis that Chlamydia promotes HIV-1 replication through the secretion of soluble factors. Although this research is still in its early development, our results suggest that conditioned medium from Chlamydia infected cells can stimulate HIV-1 production.