Project Inspiration and Description
Cancer is a generic term for a large group of diseases that can affect any part of the body. Other terms used are malignant tumors and neoplasms. One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries. It is a leading cause of death worldwide, accounting for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer.
Globally, about 1 out of 6 deaths is due to cancer
9.6 million deaths worldwide
27.5 million new cases of cancer each year by 2040.
Most of us know or have known someone who suffered from Cancer and if that’s not enough they also suffer from the Cancer treatment. Most of us have seen young women feeling shame for losing their hair, elderly people losing their independency to fatigue and men losing the ability to start a family. Just about every Cancer treatment available today comes with a lot of painful and difficult side effects; many harm the patients’ health (e.g. nausea, vomiting, pain, severe mouse, throat and bladder problems, anemia, bleeding, edema) while others affect the patient mental health (e.g. loss of memory and concentration, fatigue, sleeping problems, appetite loss, damage to sexual health) or appearance (hair loss).2
Those facts, among others, led to our goal becoming the improvement of treatments offered to cancer patients today by developing a new genetic tool, which will potentially eliminate many of the side effects associated with current cancer treatments. Can you even imagine Cancer without thinking about the side effects of the treatment? We aspire to develop a genetic tool that will stop patients from being afraid to accept treatment. Prevent patients from feeling ashamed. That will enable treatment without adding more hardship to patients who already have to deal with a difficult disease. Easing the patient's experience will aid the welfare of their families and caregivers, and help prevent the development of secondary diseases that in turn overwhelm the public health system.
Our team is part of the Immunology lab; therefore we wanted to attack Cancer through Immunotherapy.
Unfortunately Cancer Immunotherapy remains limited by the rarity of targetable tumor-specific antigens, tumor-mediated immune suppression, and toxicity triggered by systemic delivery of potent Immunomodulators. After researching these problems we learned that to overcome cancer Immunotherapy limitations, Lior Nissim et al, 2017, created the Immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators.3
Their system raised a major safety concern: the strategy relies on the destruction of an intact mRNA encoding a potentially lethal product by a mechanism operating in-trans (miRNA). Any leakiness thus poses a severe threat to all cells in the body in which promoter P1 is active, that can be translated into a potentially fatal outcome for patients.
In Nissim's work, module 1 starting point, assuming the promoter works, is 100% gene product. They use auto inhibition to try and bring it down to 0%. Then when promoter 2 is activated (module 2) its gene product prevents the inhibition of module 1. Alas even after optimization it was impossible to bring module 1 to 0%, and that leakiness is dangerous.
We are planning to solve this problem by turning the model upside down. Our module 1 starting point is the expression of only one of the exons, therefore ZERO product. Only under certain conditions, the other exon will be expressed (module 2). Then, using trans-splicing mechanism our protein will be translated. Unless both promoters are activated there will be no gene product. Thus our challenge will not be the safety of the machine, but the efficiency. Our solution insures the expression of the gene(s) of interest ONLY in cancer cells.
Our team plans to build upon Nissim's work, solve the leakiness problem and thus creating a transcriptional targeting MACHINE, the most precise of its kind, as the basis for many Cancer Immunotherapy applications designed to maximize SAFETY of treatment. Our method will revolutionize Cancer Immunotherapy and will, hopefully, reduce the suffering and mortality rate of Cancer patient.
Reference
1. Goldberger, N., Aburbeh, M., Haklai, Z. & Ministry of Health, Health Information Division. Leading causes of death in Israel 2000-2014. (2017).
2. NIH, N. C. I. Side Effects of Cancer Treatment | CDC. 1–2 (2019). Available at: https://www.cdc.gov/cancer/survivors/patients/side-effects-of-treatment.htm.
3. Nissim, L. et al. Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy. Cell 171, 1138-1150.e15 (2017).