Fondazione Carlo Grandori

Utilizzare tecniche all’avanguardia per accelerare la scoperta di nuove terapie non tossiche e personalizzate per la cura del cancro ed altre malattie.

Photograph of Carla and Carlo GrandoriCarlo Grandori blueprint

Science & Technology

New treatments are being developed around the idea that cancer subtypes require specific genes for survival, and these genes can be the focus of “targeted therapy” to treat that particular cancer. Targeted therapies block the function of genes, which are essential for the survival of cancer cells but not of normal tissues and thus represent less toxic drugs compared to conventional chemotherapy. For example, Imatinib targets the BCR/ABL gene fusion in certain Leukemias (a form of blood cancers), and specifically kills cancer cells harboring this mutation, with minor side effects.

Functional genomicsThis represents a major breakthrough, but it is a challenge to find the specific mutations within each particular cancer that act as an “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 testing the functions of thousands of genes in patient 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, and for some of these genes drugs are already available, thus making the transition from our discovery to treating the patient a potentially rapid bench-to-bedside process.

What will FCG Fund:

FCG (Cure First) plans to fund collaborative projects between scientists and clinicians to use a Functional Genomics approach to derive a “knowledge database,” “roadmap,” of cancers with which new therapies will be derived and patients may be matched to existing targeted therapies. It will lay the groundwork to enable tailored cancer treatments to individual patients with safer and more effective targeted therapies.

What do we mean by Functional Genomics?

Functional Genomics is the ability to globally interrogate the function of all genes in a given genome. Humans have ~30,000 genes, but only ~⅓ so far represent well-annotated and potentially druggable genes. Testing these ~10,000 genes is a feasible task with the use of HTS technologies (see below).

How can we study the function of each individual thousands of genes?

The answer comes from the discovery of RNA interference, which was awarded the Nobel price in 2006. In small RNA molecules that match sequences of specific genes, one can ”destroy” (i.e. interfere with) the mRNA of a given gene and thus “silence” the gene.

SiRNAThis is where the name “silencing RNAs” (siRNAs) comes from. We plan to utilize both commercially available libraries of silencing RNAs as well short RNA “hairpins” expressed from viral vectors to silence genes in cancer cells and learn which genes are essential for their survival. Because silencing RNAs are not likely to be used directly as therapeutics, this information will be utilized to pinpoint candidate genes for drug development. FCG (Cure First) will leverage a unique know-how in HTS and 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 bioinformatics tools and over 25 years of experience in cancer biology, is extremely powerful 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 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 (manuscript soon to be published). Drugs 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.

» For an example of this application see the recent publication of Dr. Grandori in the Proceedings of the National Academy of Sciences.

What do we mean by High Throughput Technologies?

HTS refers to the use of lab automation, mainly liquid-handling and read-out devices, such as robotics-operated plate readers and automated microscopes, which so far have been a privilege of large pharma. 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 testing of thousands of genes using libraries of siRNAs or shRNAs as well as of chemical entities in cancer cells (including for example all known FDA approved drugs, oncology standard of care and 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. In addition, a large focus of FCG effort will be in optimizing the testing of primary cancer samples shortly after surgical excision. Although not all cancers easily survive in tissue culture, we are beginning to learn that using low oxygen concentrations and defined culture media enhances our 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 to develop testing of patient samples to recommend appropriate treatments.