Chronic lymphocytic leukemia (CLL) is associated with the accumulation of B-cells due to decreased apoptosis. CLL is classified as aggressive (rapidly progressive) or indolent (slow-growing). This thesis sought to assess expression of G protein-coupled receptors (GPCRs), in particular GPCRs that regulate the synthesis of the second messenger 3'5'- cyclic adenosine monophosphate (cAMP), in samples from patients with CLL and in normal human B cells. Using a Taqman® GPCR array, we found that normal B-cells, indolent -CLL cells and aggressive-CLL cells express >117 GPCRs, many of which were differentially expressed in CLL-cells and in the two stages of CLL. Expression of the vasoactive intestinal polypeptide receptor 1 (VIPR1) was >700-fold greater in aggressive CLL cells than in indolent CLL-cells and normal B-cells; the agonist (VIP, 1 [mu]M) in combination with a phosphodiesterase 4/7 inhibitor (IR284, 100 nM) raised cAMP levels in both indolent and aggressive CLL-cells, but not in normal B-cells. In addition, VIP treatment (48 hr alone and together with IR284) induces apoptosis in aggressive CLL-cells. The melanocortin 2 receptor MC2R) was expressed in aggressive and indolent CLL-cells but not normal B-cells. Treatment with the MC2R agonist, adrenocorticotropic hormone (ACTH, 1 nM), in combination with IR284 induced apoptosis in aggressive CLL -cells, but not in indolent CLL-cells or normal B-cells. These results reveal that expression of particular GPCRs can provide stage-specific markers and identify novel therapeutic targets for the treatment of CLL. Moreover, the results identify a paradigm that may be useful in other disease settings

G protein-coupled receptors (GPCRs), the largest family of targets for approved drugs, are rarely targeted for cancer treatment, except for certain endocrine and hormone-responsive tumors. Limited knowledge regarding GPCR expression in cancer cells likely has contributed to this lack of use of GPCR-targeted drugs as cancer therapeutics. We thus undertook GPCRomic studies to define the expression of endoGPCRs (which respond to endogenous molecules such as hormones, neurotransmitters and metabolites) in multiple types of cancer cells. Using TaqMan qPCR arrays to quantify the mRNA expression of ∼340 such GPCRs, we found that human chronic lymphocytic leukemia (CLL) cells/stromal cells associated with CLL, breast cancer cell lines, colon cancer cell lines, pancreatic ductal adenocarcinoma (PDAC) cells, cancer associated fibroblasts (CAFs), and PDAC tumors express 50 to >100 GPCRs, including many orphan GPCRs (which lack known physiologic agonists). Limited prior data exist regarding the expression or function of most of the highly expressed GPCRs in these cancer cells and tumors. Independent results from public cancer gene expression databases confirm the expression of such GPCRs. We propose that highly expressed GPCRs in cancer cells (for example, GPRC5A in PDAC and colon cancer cells and GPR68 in PDAC CAFs) may contribute to the malignant phenotype, serve as biomarkers and/or may be novel therapeutic targets for the treatment of cancer.