Treatment of Hypoxia Resistance in Pancreatic Cancer

Garth Powis, Ph.D., Project Leader

Pancreatic cancer is one of the most aggressive adult solid tumors and patient survival at diagnosis is measured in months. A characteristic of pancreatic tumors is that they have a poorly developed blood supply leading to low oxygen levels (hypoxia). The rapid growth of pancreatice tumors alsocauses them to outstrip their blood supply which further aggravates the lack of oxygen. Hypoxia is extremely hostile environment for normal cell growth but pacreatic cancer celss have adapted to thrive in low oxygen through the increased expression of the hypoxia inducible transcription factor (HIF-1).

The long term objective of our work is to understand the redox control of pancreatic cancer growth and to use the information to develop novel and effective treatments for the disease. A short term goal is to rapidly bring a promising new drug, PX-478, to clinical trial for pancreatic cancer.

The Specific Aims of the project are:

1. To investigate redox mechanisms that control pancreatic cancer cell proliferation and apoptosis.
2. To investigate mechanisms for the inhibition of HIF-1α by PX-478.
3. To conduct a Phase I and II clinical trial of PX-478 in patients with pancreatic cancer.

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Method to Eliminate Pancreatic Cells with Specific Patterns of Mutations/Deletions

Daniel Von Hoff, M.D., Project Leader
Haiyong Han, Ph.D., Co-Leader

During the course of cancer development and growth, cancer cells accumulate genetic alterations that are either gain-of-function or loss-of-function to cellular processes. Currently, most target-based drug development approaches focus on targeting the gain-of-function alterations in oncogenes in cancer cells. However, many cancer types including pancreatic cancer have loss-of-function mutations that are more common and sometimes more important than their gain-of-function mutations. In this proposal we describe a novel drug development strategy to target the loss-of-function mutations in pancreatic cancer. The hypothesis to be tested in this proposal is that small molecular weight agents targeting specifically common loss-of-function mutations that have been shown to play a role in the tumorigenesis and progression in pancreatic cancer can be identified and developed to treat patients with pancreatic cancer.

The Specific Aims of the project are:

1. To identify genotype-selective compounds that kill pancreatic cancer cells with loss-of-function mutations in specific tumor suppressor genes.
2. To identify a series of genotype-selective compounds that kill pancreatic cancer cells with the most common combination of genetic alterations.
3. To take the compounds discovered in the first two specific aims into clinical trials as rapidly as possible.

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Validation of Amplified Genes in Pancreatic Cancer: New Sensitizing Targets for Improved Gemcitabine Therapy

Jeffrey Trent, Ph.D., Project Leader
Spyro Mousses, Ph.D., Co-Leader

Most published reports using genomic technologies applied to pancreatic cancer have led to simple cataloging of genetic changes in this devastating disease. In this study we propose an innovative research strategy that has the possibility to greatly accelerate the rate by which candidate genes in commonly are prioritized, functionally validated and clinically translated. As a secondary goal, our proposed work will also contribute valuable new knowledge about the genetics of pancreatic cancer. Finally, if successful, this project could generate valuable new targets for pancreatic therapeutics with unprecedented speed.

The Specific Aims of the project are:

1. Prioritize Amplified and Over-Expressed Genes in Pancreatic Cancer which are associated with gemcitabine sensitivity.
2. Validate the functional relevance by determining the extent to which experimental manipulation of specific gene expression can modulate sensitivity to gemcitabine.
3. Validate the clinical relevance by high throughput analysis of gene copy number and protein expression of sensitizing targets on a pancreatic cancer tissue microarray.

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Pancreas Cancer Biospecimens Repository

Michael J. Demeure, M.D., Core Director
Galen Hostetter, M.D., Co-Director

Core A (Pancreas Cancer Biospecimens Repository) will provide P01 investigators access to a wide variety of pancreatic tissues and biospecimens for translational studies in pancreatic cancer. To achieve this goal, Core A is designed to facilitate the collection and storage of pancreatic biospecimens, as well as the acquisition and database storage of essential pathologic and clinical information needed for conducting translational research. An emphasis of this effort is the creation of a unique, multi-institutional consortium, which will allow for the collection of ample numbers of diverse biospecimens relevant to pancreatic cancer.

The Specific Aims of the project are: 

1. Collect and preserve pancreatic tissue and patient body fluid (serum, pancreatic juices, blood).
2. Provide quality controlled storage and management of the Core specimen bank.
3. Collect relevant clinical and pathologic information.
4. Contribute to the development of a comprehensive database with linkage of clinical data with relevant pathologic and research findings.
5. Prioritize and distribute pancreatic tissue or other biospecimens to investigators.

Pattern Analysis and Computational Biology Core

Richard Posner, Ph.D., Core Director
David Mount, Ph.D., Co-Director
Chengcheng Hu, Ph.D., Co-Director

The pattern analysis and computational biology (PACB) core will provide expert and state of the art computational and statistical support for discovering patterns of CpG island methylation, mutation, gene amplification and gene expression that are predictive for drug sensitivity, cancer stage or clinical outcome in pancreatic cancer. In addition, they will provide validated tissue classifiers that may be used to plan future clinical trials. This core will also work out the necessary methods for searching through genome data to predict mutated or deleted tumor suppressor genes, amplified oncogenes, the best targets for therapeutic intervention, interactions among various targets and the clinical implications of hitting those targets.

Core B uses an integrated approach to data management and analysis based on the Xenobase system developed by Craig Webb in the Program of Translational Medicine (PTM) at the Van Andel Institute (VAI) to support the bedside-to bench-and back work flow that epitomizes the field of translational research. The suite serves as a portal and common interface for consolidating disparate clinical, preclinical and molecular data, and it incorporates analytical, visualization, and reporting tools, which have historically been used in a non-integrated fashion. XB-BIS allows for the bidirectional flow of real-time data, information, and extracted knowledge between the multiple clinical and laboratory research components of a translational project.

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Drug Development Core

Therapeutics Utilization

Robert Dorr, Ph.D., Core Director
Dan Von Hoff, M.D, Co-Director

The overall goal of this proposed program project is to deliver a new agent to clinical trials each year for patients with pancreatic cancer that hits a target discovered and validated in one of the five projects. This is a very aggressive goal and it will take a very efficient and concentrated effort, particularly of this Core to attain that goal. This Drug Development Core has the overall responsibility to provide the drug development tools and services to develop a new therapeutic based on a target found in one of the five projects.

The Specific Aims of the project are: 

1. To provide compound libraries, robotic and other services for screening those libraries to find a lead agent against a new target.
2. To provide synthetic chemistry capabilities as well as molecular modeling capabilities to optimize activity of lead compounds.
3. To provide formulation capabilities for any lead or candidate compounds.
4. To provide in vitro and in vivo testing in a variety of pancreatic cancer models as needed for each lead.
5. To provide pharmacologic assays and pharmacodynamic assays as needed for each project.
6. To provide initial toxicology studies of drug candidates produced by each project.
7. To provide a regulatory package (IND) for submission to the regulatory authorities to initiate a phase I trial of the new target. This package will include a complete development plan for the compound.
8. To secure a long-term commercial sponsor for each compound so the compound will proceed through phase I, II, and III clinical trials.

Evaluation and Administrative Core

Daniel Von Hoff, M.D., Core Director

Program project grants, including the present submission, have several unique features that require added attention to evaluation and administration.

These features include:

• Multiple projects that have different emphases but a common goal.
• Investigators of diverse backgrounds - particularly the investigators in this PO1, which is a "bench to bedside" proposal.
• Tissue collections from a variety of institutions.
• Important frequent oversight to move new targets from the bench to the bedside.

The Evaluation and Administration Core will be responsible for supporting these unique features of the program project, as well as the routine day-to-day tasks that are associated with a large, diverse, multiple project grant.

This Core will provide the following services:

• Will provide essential administrative support to all the projects and cores.
• Maintain scientific oversight of each Project and for the entire program through weekly meetings of Drs. Von Hoff, Powis, and Green, and the leader and personnel of one of the Projects in rotation, as well as monthly meetings of the Executive Committee.
• Coordinate monthly videoconferences between the AZCC, TGen, and the collaborators.
• Schedule twice a year meetings of the External Scientific Advisory Board (one of these at the retreat - see below) and additional consultation as needed or requested by the External Scientific Advisory Board.
• Organize a yearly retreat.
• Oversee accounting and budget administration for all parts of this PO1.
• Maintain detailed records on program activities.
• Organize participant travel and help prepare participants for their presentations at national meetings.