Personalized therapy for pancreatic cancer: Do we need better targets, arrows, or both?

Pancreatic cancer is predicted by the Pancreatic Cancer Action Network to soon become the 2nd leading cause of cancer related deaths in this country. This cannot be attributed to a lack of resources focused on interrogating the genomic landscape of pancreatic cancer genomes. Additionally, a large number of researchers and federal dollars have been directed towards inhibiting the most frequent genetic lesion in pancreatic cancer, Kras. Even with these advances, cytotoxic chemotherapy is currently the best option for patients with metastatic disease. Besides developing better early detection strategies, translating our knowledge of the molecular aspects of pancreatic cancer to the clinic via a targeted, personalized medicine approach may be the best way to dramatically improve patient outcomes. Herein, we briefly describe the scope of the problem in targeting pancreatic cancer on both the cellular and molecular levels. We also outline some promising, ongoing efforts to develop better therapeutic interventions for this deadly disease. For instance, we discuss novel strategies to target molecules and pathways that go beyond targeting genetic mutations and the level of transcriptional gene regulation. Finally, we summarize a clinical trial that is designed to answer the question whether with the available arsenal of drugs and molecular targets, can we now "personalize" therapy for pancreatic cancer patients?

ELR+ CXC chemokines and oncogenic Ras-mediated tumorigenesis.

The small GTPase Ras is mutated to remain in the active oncogenic state in one-third of human cancers, thereby promoting tumorigenesis. It has recently come to light that one consequence of oncogenic Ras signaling is secretion of cytokines vascular endothelial growth factor (VEGF), interleukin 6 (IL6), hCXCL1 (Gro-alpha) and hCXCL8 (IL8). As the latter two belong to the ELR+ Cys-X-Cys (CXC) chemokine family, we investigated whether the entire family of ELR+ CXC chemokines plays a role in oncogenic Ras-mediated tumorigenesis. We now demonstrate that oncogenic Ras induced the expression and secretion of the ELR+ CXC chemokine family in different tumorigenic human cells and that these chemokines are elevated in tumor specimens. Moreover, genetic ablation of the common receptor for these chemokines, mCXCR2, reduced oncogenic Ras-driven tumorigenesis in mice. Taken together, we suggest that oncogenic Ras induces the secretion of the ELR+ CXC chemokine family to promote tumorigenesis. This chemokine signature may identify the presence of Ras activation in cancer and perhaps even serve as targets for oncogenic Ras-driven tumor cells.

Oncogenic ras-induced expression of cytokines: a new target of anti-cancer therapeutics.

The Ras family of small guanosine triphosphatases normally transmit signals from cell surface receptors to the interior of the cell. Stimulation of cell surface receptors leads to the activation of guanine exchange factors, which, in turn, convert Ras from an inactive GDP-bound state to an active GTP-bound state. However, in one third of human cancers, RAS is mutated and remains in the constitutively active GTP-bound state. In this oncogenic state, RAS activates a constellation of signaling that is known to promote tumorigenesis. One consequence of this oncogenic RAS signal in cancer cells is the upregulation of the cytokines interleukin (IL)-6, IL-8, and chemokine growth-regulated oncogene 1 (GRO-1). We review the evidence supporting a role for these cytokines in oncogenic RAS-driven solid tumors.

A genetically defined normal human somatic cell system to study ras oncogenesis in vivo and in vitro.

Transgenic mice, cultured murine cells, and human cancer cell lines have widely been used to study Ras oncogenesis. Although extremely valuable systems, they could not be used to study Ras function in genetically defined human cells. In this regard, Ras is required for tumor formation in normal human somatic cells expressing SV-40 T/t antigens, which inactivate the tumor suppressors p53 and Rb and activate the oncogene c-Myc, and hTERT, the catalytic subunit of telomerase. Such a system allows not only the general requirements of Ras to be dissected in matched cells from different organisms or tissues but also the individual pathways required for tumor growth to be defined in human cells. This review will detail the methods of creating stable T/t Ag, TERT, Ras-expressing cell lines, as well as commonly used techniques of soft agar and xenograft tumor formation.