MORE ABOUT THE SCIENCE AND TECHNOLOGY BEHIND CURE FIRST

BLOCKING GENES

Dr Carla Grandori's talk at the 2014 Institute for Systems Biology International Symposium on Personalized Medicine.

New treatments are being developed around the knowledge that cancer subtypes require specific genes for survival and that these genes can be the focus of “targeted therapy.” Targeted therapies block genetic functions which are essential for the survival of cancer but not for the viability of normal tissues.

Focusing on these blocking actions can lead to the development of drugs which produce less overall toxicity compared to those delivered via conventional chemotherapy.  For example, the drug Imatinib specifically targets the BCR/ABL gene fusion in certain leukemias and kills cancer cells harboring this mutation while producing only minor side effects.

Chris Kemp and Carla Grandori April 2016 talk at Microsoft:

High Throughput Functional Testing of Patient Derived Cancer Cells to Identify and Validate Novel Druggable Targets.

Targeting specific genes represents a major breakthrough but it is a challenge to find the distinct mutations within each particular cancer that act as its “Achilles heel,”  especially since most cancers have hundreds or thousands of genetic changes. We propose to overcome this challenge by utilizing an innovative approach that allows us to test the functions of thousands of genes in tumor samples using small RNA probes that assess the importance of each gene with respect to the individual cancer in question. Thousands of potential targeted therapies exist in the form of catalogued chemicals. In the

case of some of the genes we are looking to block, drugs are already available, making the transition from our discovery to treating the patient a potentially rapid bench-to-bedside process.

FUNCTIONAL GENOMICS

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Functional genomics describes the ability to globally interrogate the function of all the genes in a given genome. Humans have ~30,000 genes, but only ~one-third of those genes currently represent well-annotated and potentially druggable targets. Testing the functions of these 10,000 genes is a feasible task with the use of High-Throughput Screening (HTS) technology. Once we determine the function of the genes which a cancer needs to survive, we can use HTS to test drugs and drug combinationsto assess the most effective way to disable the function of the incriminating gene.

HOW DO WE STUDY THE FUNCTION OF EACH INDIVIDUAL’S GENES?

The answer comes from looking at RNA interferences, the discovery of which was awarded a Nobel Prize in 2006. Using small RNA molecules that match the sequences of specific genes, we can “destroy” (il.e. interfere with) the mRNA of a given gene and thus “silence” the gene. This is where the name “silencing RNAs” (siRNA) comes from.

We plan to utilize both commercially available libraries of siRNAs as well as short RNA “hairpins” expressed from viral vectors to silence genes in cancer cells and to learn which genes are essential for a cancer’s survival. Because siRNAs are not likely to be used directly as therapeutics, the information from our investigations will be utilized to pinpoint candidate genes for drug development.  Cure First will leverage a unique know-how in HTS with the Functional Genomics pioneered in a small biotech firm in Seattle, Rosetta Inpharmatics, and further optimized at the University of Washington under the direction of Dr. Carla Grandori.

This state-of-the-art technology, combined with bioinformatic tools and over 25 years in cancer biology, is an extremely powerful tool for identifying novel targets for drug development.

For example, utilizing HTS siRNA screening, Dr. Grandori has identified over 100 potentially druggable genes that when inhibited by siRNAs caused the death of cells that overexpress the MYC oncogene but do not cause harm to normal cells. These genes are referred to as “synthetic lethal” with the MYC oncogenes(ms. soon to be published). Drugs targeted against these genes have the potential to treat many cancers where the activity of MYC is altered. A similar approach can be utilized to identify “synthetic lethal” genes for other commonly occurring cancer-causing genes.

See the recent publication of Dr. Grandori in the “Proceedings of the National Academy of Sciences.”

WHAT DO WE MEAN BY HIGH-THROUGHPUT SCREENING (HTS) TECHNOLOGY?

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HTS refers to the use of lab automation, mainly liquid-handling and read-out devices such as robotic-operated plate readers and automated microscopes which have so far been the exclusive privilege of large pharmaceuticals. These instruments enable us to rapidly and accurately dispense cells and measure their growth and many other parameters (such as cell death, differentiation, and pathway activity) in miniaturized conditions (384- and 1536 well plates).

This approach enables the testing of thousands of genes using libraries of siRNAs or shRNAs. We can also use HTS to test the effect on cancer cells of all known FDA-approved drugs, the oncology standard of care, as well as targeted therapies.

WHAT CELLS AND MODEL SYSTEMS WILL BE UTILIZED

Dr. Grandori has optimized a human cell system where isogenic cells, with or without a mutated oncogene or tumor suppressor pathway, can be employed. Cure First work to optimize the testing of primary cancer samples shortly after surgical excision. Athough not all cancers easily survive in tissue culture, we are beginning to develop techniques which have success in maintaining the viability of cancer cells in culture.

The combination of drug testing with RNA interference screening will produce a functional classification of cancers never known before. This will constitute key knowledge for targeted therapeutic approaches and will lay the groundwork whereby we can develop testing of patient samples in order to recommend safe, effective and less-toxic treatments.

Link to publications

I support Cure First because I see it as one of the most logical ways to identify new treatments and cures for patients with cancer. It truly allows the promise of personalized medicine to become a reality.
— Dr. Barbara Goff, MD, Professor and Division Director, Gynecologic Oncology, University of Washington