Genitourinary Oncology Laboratory

Adam S. Kibel, M.D.
Professor

Division of Urology Faculty Page

Siteman Cancer Center Faculty Page

kibela@wudosis.wustl.edu

Director of Urologic Oncology
Division of Urologic Surgery

The genitourinary oncology laboratory focuses on the study of the genetics of urologic malignancies, specifically prostate cancer. We are currently exploring three avenues of research. The first is identification of tumor suppressor genes critical to the development of prostate carcinoma. The second is the role of common polymorphic variants in increasing individuals’ risk of prostate carcinoma. The third is molecular signatures of response to therapy for prostate cancer.

Tumor Suppressor Genes – It is currently accepted that alterations in specific genes, such as p53 and VHL, are responsible for the transformation of normal cells into cancerous cells. These gene alterations allow the cell to develop the ability to grow more rapidly, resist apoptosis, evade the immune system, invade the basement membrane and eventually grow at a distant site. This step-wise progression from normal cell to metastatic deposit can be explained by a series of genetic alterations that produce the metastatic phenotype. Although a rough pattern of specific gene alterations is emerging for certain cancers such as breast or colon cancer, current genetic understanding of prostate cancer is at a more primitive level and few prostate cancer-specific patterns of gene alterations have been identified. Our hypothesis is that a prostate cancer-specific pattern of gene alterations exists. In order to identify the pattern of gene alteration, DNA, RNA and proteins from tumors, xenografts and cell lines are analyzed for mutation, hypermethylation and altered expression. Potential genetic alterations are then interrogated for functional significance. We believe that the identification of frequently altered genes will eventually provide a basis for more effective molecular-alteration-based prognostic indicators and targeted therapy in prostate cancer.

Polymorphic Variants – While the identification of major cancer susceptibility genes, such as p53 and VHL, has provided important insights into the molecular basis of cancer, germ line mutations in such genes are rare, and account for increased cancer risk in only a small segment of the population. On the other hand, common polymorphic variants, which alone do not cause cancer, can in certain environments or in concert with other genetic alterations, influence tumor development or progression. These minor susceptibility genes are prevalent in the population at large and therefore have the potential to influence disease progression in a large percentage of the population in concert with environmental exposures. Examining polymorphic variants in populations of patients with and without prostate carcinoma will identify populations at risk for the disease who can be screened and/or treated aggressively and therefore translate into improved patient care.

Molecular Signatures of Response – Currently response to therapy is predicted by stage and grade. In rare cases a serologic marker, such as PSA in prostate cancer, provides additional information. In general, these clinical variables predict a risk of relapse irrespective of therapy and are more of a reflection of the cancer than the treatment. Molecular analysis of serum, plasma, somatic DNA and tumor DNA provides an opportunity to not only determine signatures of disease, but also can serve as signature of response to therapy. For example, expression profiles of genes responsible to metabolism of chemotherapeutic agents or DNA repair may be altered in tumors which respond (or fail to respond) to a particular treatment. In addition, polymorphic variants present in the host genome can result in altered expression of specific genes critical of response to therapy. Analysis of these variants may also predict response. We are currently analyzing tumors and host genome to determine if response modifiers can be identified.

Current Grant Support

1) Midwest Stone Grant, 2003-2006
Feasibility Study of Prostate Tumor Localization for Focal Cryoablation of Prostate Carcinoma

2) R01 NCI Research Grant (R01 CA112028), 2005-2010
Cell Cycle Variants and Metastatic Prostate Cancer Risk

3) Sanofi-Aventis, 2006-2008
Gene Expression Profiling in Prostate Carcinoma: Identification of Molecular Targets of Docetaxel

Current personnel:

• William Wu, M.D.
• David Berger, MD
• Alex Klim, R.N.
  

Recent papers:
Noonan-Wheeler FC, Wu W, Roehl KA, Klim A, Haugen J, Suarez BK, Kibel AS. Association of hereditary prostate cancer gene polymorphic variants with sporadic aggressive prostate carcinoma. Prostate. 2006;66:49-56.

Kibel AS. Single nucleotide polymorphisms: early diagnosis and risk assessment. Urol Oncol 2006;24:224-2230.

Kibel AS, Huagen J, Guo C, Isaacs WB, Yan Y, Pienta KJ, Goodfellow PJ. Expression mapping at 12p12-13 in advanced prostate carcinoma. Int J Cancer. 2004;109:668-672.

Kibel AS, Faith DA, Bova GS, Isaacs WB. Xq27-28 deletions in prostate carcinoma. Genes Chromosomes Cancer. 2003;37:381-388.

Kibel AK, Suarez BK, Belani J, et al. CDKN1A and CDKN1B polymorphisms and risk of advanced prostate carcinoma. Cancer Research. 2003;63:2033-2036.

Kibel AS, Faith DA, Bova GS, Isaacs WB. Mutational analysis of ETV6 in prostate carcinoma. Prostate. 2002;52:305-310.

Yan Y, Andriole GL, Humphrey PA, Kibel AS. Patterns of multiple recurrences of superficial (Ta/T1) transitional cell carcinoma of bladder and effects of clinicopathologic and biochemical factors. Cancer. 2002;15:1239-1246.

Kibel AS, Christopher M, Faith DA, et al. Methylation and mutational analysis of p27kip1 in prostate carcinoma. Prostate. 2001;48:248-253.

Kibel AS, Faith, DA, Bova GS, et al. Loss of heterozygosity at 12p12-13 in primary and metastatic prostate adenocarcinoma. Journal of Urology. 2000;164:192-196.

Kibel AS, Isaacs WB. G1/S cell cycle proteins as markers of aggressive prostate carcinoma. Urology. 2000;55:316-322.

Jackman SV, Kibel AS, Ovuworie CA, et al. Familial calcium stone disease: TaqI polymorphism and the vitamin D receptor. Journal of Endourology. 1999;13:313-316.

Kibel AS, Freije D, Isaacs WB, et al. Deletion mapping at 12p12-13 in metastatic prostate cancer. Genes Chromosomes Cancer. 1999;25:270-276.

Kibel AS, Schutte M, Kern SE, et al. Identification of 12p as a region of frequent deletion in advanced prostate cancer. Cancer Research. 1998;58:5652-5655.