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Menlo Park

Lab website



Diagramming Disease Networks with Chemical and Biological Tools



We are diagramming the interconnected signaling networks underlying cancer and neurodegenerative diseases using chemical and biological tools. Our approach is to design high-throughput screens in mammalian cells that allow us to test tens of thousands of small organic molecules and small interfering RNAs for their ability to affect cellular phenotypes associated with oncogenic signaling or neurodegeneration. These screens reveal reagents that are used to identify specific proteins and genes that act as the critical regulators of cellular disease pathologies. We define the molecular function of these critical regulators using protein biochemistry, molecular cell biology and chemical synthesis.



Potential research projects include:



• 
  identifying the protein targets and signaling pathways affected by novel compounds we have discovered in screens related to cancer and neurodegeneration
  
• 
  creating and executing high-throughput screens related to oncogenic signaling and neurodegeneration to identify novel compounds and genes of interest
  
• 
  defining protein ligation events (ubiquitylation, sumoylation, etc) associated with specific disease proteins
  
• 
  creating novel photoaffinity reagents, fluorescent sensors and chemical libraries

VNP40541 is an anticancer agent in late stage preclinical development. It exhibited potent anticancer activities in preclinical studies and is activated under hypoxic (low oxygen) conditions.






Q: What is VNP40541 and how does it work?
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A: VNP40541 is a hypoxia-selective anticancer agent that is being evaluated in preclinical studies. Hypoxic, or low-oxygen, tumor cells, representing a fraction of the whole tumor, are resistant to cancer treatment modalities including radiation and chemotherapy. Complete regression of solid tumors requires strategies that eradicate tumor cells within the hypoxic regions. VNP40541 converts to a cytotoxic compound only under hypoxic conditions. VNP40541 remains relatively inactive under oxic conditions. Upon activation in hypoxic conditions, VNP40541 liberates the DNA chloroethylating species 90CE, which is the same active metabolite released by Cloretazine® (VNP40101M). 90CE produces interstrand DNA cross-links that are difficult to repair and are toxic to cells.  VNP40541is designed to be selective for tumor cells. Since almost all solid tumors contain hypoxic regions, it is expected that VNP40541 will work well in combination with other anticancer agents.
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Q: What is the status of VNP40541 product development?
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A: Human clinical trials are expected to commence in 2007.
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TAPET® : Tumor Amplified Protein Expression Therapy, is a modified Salmonella vector used to deliver anticancer agents directly to tumors.





Q. What is TAPET® and how does it work?



A: TAPET® is live attenuated Salmonella bacteria that
has been shown in animal studies to selectively accumulate in tumor tissue
over normal tissue. Vion seeks to employ TAPET® technologies as a means
of delivering anticancer therapy directly to tumors.

Q. Why and how does TAPET® accumulate in tumors?

A: The TAPET® bacteria move throughout the body but
are generally destroyed by the immune system as they move through normal
body tissue. Once they penetrate a tumor, however, tumor-produced substances
are thought to inhibit the immune system, thereby permitting replication
and accumulation of the bacteria. Tumors also have areas of rapid cell
turnover and low oxygen tension, which provide nutrients and favorable
growth conditions for the bacteria. TAPET® bacteria will replicate
in the tumor by doubling every 30 to 40 minutes, growing to about 100
million to1 billion bacteria per gram of tumor tissue. This represents
1000-fold or more greater concentration of bacteria in tumors compared
to normal tissues.

Q. How will TAPET® treat cancer?

A: Conventional cancer treatments are limited by the amount
of drug that reaches the tumor, and by the toxicities of the drug, since
normal tissues are exposed to similar or higher concentrations of drug
than tumor tissue. Therefore, the cancer drug must be given intermittently
to allow normal tissues to recover, but during this interval the tumor
also recovers from the effects of the cancer drug. The accumulation of
TAPET® bacteria in tumor, and the much higher numbers of bacteria
in tumor compared to normal tissue, suggests that any cancer fighting
agent produced by the bacteria will also be at much higher concentrations
in the tumor compared to normal tissue. Furthermore, because the bacteria
remain in the tumor for prolonged periods, the delivery of the cancer-fighting
agent is continuous.



Vion scientists are taking advantage of the high numbers of bacteria that accumulate
in tumors by engineering the bacteria to produce cancer-fighting substances.
These armed bacteria have already been shown to produce large amounts of a
cancer-fighting substance in animal tumors.

Blueshift Biotechnologies, Inc.

245 Santa Ana Court

Sunnyvale, CA 94085



Phone: 408-773-1050

Fax: 408-773-1164

E-mail:

info@blueshiftbiotech.com

For media  inquiries related to research analysts, industry expertise or economics, please contact

Jackie Braden 
Media Relations 

Corporate Communications

Toronto

Office: 416-974-2124, Email: jackie.braden@rbc.com

For media inquiries related to the U.S., Asia and Australia please contact:

Kevin Foster 
Head of Communications, U.S.

Corporate Communications

New York 

Office: 212-428-6902, Email: Kevin.Foster@rbccm.com

Susan McDougall

Director, Communications, CIBC World Markets

Tel: 416-980-4047

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