Tel Aviv University system delivers therapy at site of mantle cell lymphoma

With a median survival rate of just five to seven years, MCL is considered deadly and available therapies are scarce.

By JUDY SIEGEL-ITZKOVICH
Doctor with sample (photo credit: INGIMAGE)
Doctor with sample
(photo credit: INGIMAGE)
New research at Tel Aviv University offers significant hope of curing the most aggressive and presently incurable blood cancer called mantle cell lymphoma (MCL) and others like it. The promising and innovative system was found to successfully halt the proliferation of a cancer-related protein in white blood cells in both animal models and samples taken from MCL patients.
The study has just been published in the early edition of the Proceedings of the [US] National Academy of Sciences.
The research was led by Prof. Dan Peer of TAU ’s department of cell research and immunology and conducted by TAU doctoral students Shiri Weinstein and Itai Toker, in collaboration with Prof. Pia Raanani of Rabin Medical Center-Beilinson Campus in Petah Tikva and Prof. Arnon Nagler of Sheba Medical Center at Tel Hashomer.
With a median survival rate of just five to seven years, MCL is considered deadly and available therapies are scarce. Some 3,000 Americans and a few dozen Israelis are diagnosed with it in an average year.
Despite progress in personalized therapies to treat metastases elsewhere in the body, systemic therapeutic drug delivery to cancerous blood cells continues to challenge the world of cancer research.
“MCL has a genetic hallmark,” said Peer. “In 85 percent of cases, the characteristic that defines this aggressive and prototypic B-cell lymphoma is the heightened activity of the gene CCND1, which leads to the extreme overexpression, a 3,000- to 15,000- fold increase of the protein Cyclin D1, which controls the proliferation of cells. Downregulation of Cyclin D1 using siRNA s is a potential therapeutic approach to this malignancy.”
The research validates a novel strategy developed two years ago in Peer’s lab that involved small interfering RNA s (siRNA s). The radically different new delivery system harnesses nanoparticles coated with “GPS” antibodies that navigate toward the location of the cancerous cells, where they then offload Cyclin D1-blockers in the form of siRNA s.
For the purpose of the research, the scientists designed lipid-base nanoparticles (LNPs) coated with anti- CD38 monoclonal antibodies that were taken up by human MCL cells in the bone marrow of affected mice. When loaded with siRNA s against Cyclin D1, the targeting LNPs induced gene silencing in MCL cells and prolonged the survival of tumor-bearing mice with no observed adverse effects.
“In MCL, Cyclin D1 is the exclusive cause of the over-production of B lymphocytes, the cells responsible for generating antibodies,” said Peer. “This makes the protein a perfect target for RNA therapy by siRNA s. Normal, healthy cells don’t express the gene, so therapies that destroy the gene will only attack cancer cells. The RNA interference we have developed targets the faulty Cyclin D1 within the cancerous cells. And when the cells are inhibited from proliferating, they sense they are being targeted and begin to die off.”
The new research highlights the therapeutic potential of Cyclin D1 therapy in MCL and presents a novel RNA delivery system that opens new therapeutic opportunities for treating MCL and other similar B-cell malignancies, the scientists said.
“This research makes a definite contribution to the revolution of personalized medicine, whereby you tailor the drug based on the genetic profile of patient,” said Peer. “In this case, MCL is a disease with a specific genetic hallmark, so you can sequence the patient to identify the mutation(s) and design RNA blockers to be placed inside a nanovehicle."
“While the targeting antibodies - the ‘GPS’ - can be used to target many different B-cell malignancies, the drug itself is designed to silence this specific disease. However, the delivery system can be used to accommodate any disease with a genetic profile. This could be the future. We are seeing it happen before our very eyes.”