The Sol Goldman Pancreatic Cancer Research Center

Islet Cell Tumor Research at Johns Hopkins

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Figure 1 - click for larger

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Figure 2 - click for larger

In addition to the prolific clinical service component geared towards islet cell tumors, Johns Hopkins also has an active research program studying this rare cancer variant. These studies are conducted in the laboratory of Dr. Anirban Maitra. Over the years, the Maitra laboratory has published many pioneering studies in the molecular biology of islet cell tumors, for example, using cutting edge "Gene Chip" (microarray) technology and other platforms 1-8. Thus, we were the first to report a microarray analysis of islet cell tumors compared to normal islet cells in the pancreas 1. This study identified several abnormal pathways (genes that are abnormally "turned on" or "turned off") which result in the formation of islet cell tumors from normal islets (Figure 1).

A more recent study by the Maitra laboratory specifically compared the microarray data across thousands of genes in islet cell tumors with metastases versus islet cell tumors that were localized to the pancreas 2. The importance of this study cannot be overstated, as there are few clinical criteria besides the evidence of frank metastases, that can reliably predict which islet cell tumors will spread from the pancreas and which will remain localized. We identified two genes (the Met proto-oncogene and insulin-like growth factor binding protein-3 [IGFBP-3]) that were expressed at very high levels only in metastatic tumors, but at significantly lower levels in tumors that did not metastasize (Figure 2).

It is postulated that overexpression of these proteins could play a role in the dissemination of islet cell tumors from the pancreas. In this context, it is important to note the abnormal expression of Met proto-oncogene has been associated with metastases in other tumor types 9. Further, there are drugs targeted against Met that are already in clinical trials 10, and these agents could conceivably be used as a novel therapeutic strategy in patients with aggressive islet cell tumors, particularly if the metastases are Met-positive.

On the same lines, our group has identified overexpression of two proteins that "crosstalk" with each other in highly aggressive (metastatic) islet cell tumors 3, 4. These two proteins known as vascular endothelial growth factor C (VEGF-C) and neuropilin 1(NRP1) are a pair of ligand and receptor that bind to each other and establish a "feed forward" loop that drives tumorigenesis in islet cell neoplasms. Of great interest, there are now therapeutic strategies available to block the interaction between VEGF-C and NRP, thus abrogating this "feed forward" loop, and potentially blocking islet cell tumor progression 11. To the best of our knowledge, we remain the only group to have demonstrated this relationship in islet cell tumors, and hope to translate these findings into actuarial patient benefit.

Future Directions in Islet Cell Tumor Research: Creating personalized Therapies for Aggressive Disease
The Hopkins group is now uniquely poised to perform cutting edge research into understanding the genetic basis of islet cell tumors. In the past year, we have collaborated with the laboratory of Drs. Bert Vogelstein and Kenneth Kinzler (the two most highly cited scientists in all of science) to sequence the entire genome of pancreatic adenocarcinomas (the other major tumor type in the pancreas) 12. This sequencing effort, which was funded by private philanthropy, has allowed us to sequence every single gene known in the human genome in a series of 24 pancreatic adenocarcinomas and elucidate the genetic fingerprint of this lethal malignancy.

Why is this project so important for pancreatic adenocarcinoma?

  1. Using this data, scientists at Hopkins and the world over can now develop molecularly targeted therapies specifically directed at genetic defects found in pancreatic adenocarcinoma cells, without harming normal cell types. Most importantly, specific therapies can tailored to specific tumors that harbor these genetic defects, thus maximizing efficacy.
  2. Scientists can utilize this genetic data to develop better tumor markers which can be used for earlier diagnosis of pancreatic adenocarcinomas, as well as monitoring patients for tumor recurrence.
  3. Scientists can use this genetic data to develop better disease models (mouse models) which can be used for testing new drugs or for improving our understanding of why pancreatic adenocarcinomas arise in the first place.

The Maitra laboratory has generated a unique tissue resource of islet cell tumors that will now permit us to extend this sequencing effort to this rare tumor type. Specifically, they have generated "xenografts" (human tumors grown in mice) from surgically resected islet cell tumors and metastases at Hopkins. In xenografts, the human DNA is exclusively derived from the tumor, without contamination by DNA from normal human cells (any normal cells are mouse in origin), and therefore, it is possible to generate large amounts of "pure" tumor-specific DNA required for such mega-sequencing projects. In addition, we also have access to a large number of surgically resected islet cell tumors in our tissue bank, which can be purified using a method known as "microdissection" for extracting relatively pure tumor-specific DNA. In summary, we have the unique technology (in collaboration with the Vogelstein laboratory) as well as the tissue resources (generated by the Maitra laboratory) to make a major impact in the gravely understudied area of islet cell tumors. But we need YOUR help, as federal funding for this disease is minimal to non-existent due to its rarity.

  1. Maitra A, Hansel DE, Argani P, et al. Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays. Clin Cancer Res 2003;9(16 Pt 1):5988-95.
  2. Hansel DE, Rahman A, House M, et al. Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. Clin Cancer Res 2004;10(18 Pt 1):6152-8.
  3. Hansel DE, Rahman A, Hermans J, et al. Liver metastases arising from well-differentiated pancreatic endocrine neoplasms demonstrate increased VEGF-C expression. Mod Pathol 2003;16(7):652-9.
  4. Hansel DE, Wilentz RE, Yeo CJ, Schulick RD, Montgomery E, Maitra A. Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract. Am J Surg Pathol 2004;28(3):347-56.
  5. Hansel DE, House MG, Ashfaq R, Rahman A, Yeo CJ, Maitra A. MAGE1 is expressed by a subset of pancreatic endocrine neoplasms and associated lymph node and liver metastases. Int J Gastrointest Cancer 2003;33(2-3):141-7.
  6. Rahman A, Maitra A, Ashfaq R, Yeo CJ, Cameron JL, Hansel DE. Loss of p27 nuclear expression in a prognostically favorable subset of well-differentiated pancreatic endocrine neoplasms. Am J Clin Pathol 2003;120(5):685-90.
  7. House MG, Herman JG, Guo MZ, et al. Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms. Surgery 2003;134(6):902-8; discussion 9.
  8. House MG, Herman JG, Guo MZ, et al. Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Ann Surg 2003;238(3):423-31; discussion 31-2.
  9. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003;4(12):915-25.
  10. Abidoye O, Murukurthy N, Salgia R. Review of clinic trials: agents targeting c-Met. Rev Recent Clin Trials 2007;2(2):143-7.
  11. Pan Q, Chanthery Y, Liang WC, et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer cell 2007;11(1):53-67.
  12. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science (New York, NY 2008;321(5897):1801-6.
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