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Human Immunology: immune responses to
cancer
Colorectal cancer: the role
of immune responses in tumor aggressiveness, metastasis, and racial
disparities. Two different forms of genomic instability are associated
with colorectal cancer. Chromosomal instability is the more common form, found
in about 80-85% of spontaneous tumors. Microsatellite instability (MSI) is
found in ~15-20% of colorectal cancers. These tumors are associated with
greater survival in patients because the tumors appear to be less aggressive
and metastasize less frequently. The observation that MSI tumors have higher
numbers of infiltrating CD8+ lymphocytes has led to the hypothesis that immune
responses contribute to the decreased aggressiveness of MSI tumors. Recent
studies have confirmed that immune responses in colorectal cancer improve
patient prognosis no matter what type of genomic instability is observed.
Interestingly, a race disparity is also observed in colorectal cancer with a
higher incidence occurring in blacks. Black patients tend to have more
aggressive disease with a worse prognosis than whites as well. In a study using
a colon cancer tumor bank containing ~50% tumors from black patients, John
Carethers and his colleagues at UCSD have demonstrated that black patients with
colorectal cancer exhibit 50% less MSI than whites. In collaboration with Dr.
Carethers, we have hypothesized decreased immune responses in black patients
may at least in part explain the increased tumor aggressiveness and decreased
patient survival that are observed in black patients. Using the same colon cancer
tumor bank used by Dr. Carethers and his colleagues, we are asking if the number
of immune cells infiltrating tumors from blacks differs from what is observed
in whites. In addition, we are investigating the type and quality of the immune
response present in colorectal cancer to further understand how it protects
patients and to determine if it varies by race, thus contributing to the racial
disparities observed.
In a related project, we are collaborating with Dr. Shelli McAlpine in the
Department of Chemistry at SDSU to identity compounds that might be effective
chemotherapeutic agents against MSI tumors. These tumors, while less aggressive
than others, are completely resistant to the standard treatment of choice,
5-fluorouracil. It is important to identify and develop, therefore, new
chemotherapeutic agents against this type of cancer. We have in the past assisted
Dr. McAlpine and her students with the biological testing of the compounds
synthesized in her laboratory and this collaboration has already resulted in
several publications and promising leads. Future studies will include the
development of a mouse colon cancer model that will be used to test the
efficacy of drugs synthesized in her lab to treat animals with naturally
occurring colon cancer.
Representative Recent Publications:
Xu. T, S. Maloy and K. L. McGuire. 2009. Macrophages
influence Salmonella host-specificity in
vivo. Microbial Path. 47:212-222.
Obtruva, K., G. H.
Lushington, D. V. Velde, K. L. McGuire and S. R. McAlpine. 2008. Comprehensive
study of Sansalvamide A derivatives and their structure-activity relationships
against drug-resistant colon cancer lines. J. Med. Chem. 51:530-544.
Pan, P.-S., K. L,
McGuire and S. R. McAlpine. 2007. Identification of compounds potent against
pancreatic cancer cell lines. Bioorg. Med. Chem. Lett. 17:5072-5077.
Obtruva, K., K. L.
McGuire and S. R. McAlpine. 2007. A novel platform targeting drug-resistant
colon cancers. J. Med. Chem. 50:1999-2002.
Giacalone, M. J., J.
C. Zapata, N. L. Berkley, R. A. Sabbadini, Y-L.
Chu
*,
M. S. Salvato and K. L McGuire. 2006. Immunization with non-replicating E. coli minicells delivering both
protein antigen and DNA protects mice from lethal challenge with Lymphocytic
Choriomeningitis Virus. Vaccine 12:2279-2287.
Giacalone,
M. J., R. A. Sabbadini, A. L. Chambers, S. Pillai, N. L. Berkeley, M. W. Surber
and K. L. McGuire. 2006. Immune responses elicited by bacterial minicells
capable of simultaneous DNA and protein antigen delivery. Vaccine 24:6009-6017.
Styers,
T. J.; A. Kekec, R. Rodriguez, J. D. Brown, J. Cajica, P.-S. Pan, E. Parry, C.
L. Carroll, I.
Medina
, R. Corral, S. Lapera, K.
Otrubova, C.-M. Pan, K. L. McGuire and S. R. McAlpine. 2006. Synthesis of
Sansalvamide A derivatives and their cytotoxicity in the colon cancer cell line
HT-29. Bioorg. Med. Chem. 14/16:5625-5631.
Otrubova,
K., T. J. Styers, P.-S. Pan, R. Rodriguez, S. R. McAlpine and K. L. McGuire.
2006. Synthesis and novel structure-activity relationships of potent
Sansalvamide A derivatives. Chem. Commun. 2006:1033-1034.
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