The Technion-Israel Institute of Technology and New York University Langone Medical Center have initiated a joint cancer research project, targeting the most dangerous form of skin cancer, metastatic melanoma, and mesothelioma, a rare cancer that develops in the protective lining of the lungs and other internal organs.
In the first joint collaboration, US and Israeli researchers will test the ability of a nanotechnology based on so-called “nanoghosts” to deliver the promising treatments.
In earlier studies, Technion researchers took a stem cell, removed its contents and then shaped a piece of the cell’s outer membrane into a vehicle to deliver treatments into the brain.
The idea was to borrow the stem cell’s outer membrane to home in on cancer cells.
As a fragment of the former stem cell’s membrane, the nanoghost encompasses particular mechanisms that slow it enough to traverse the barrier that filters blood flowing into the brain and which keeps most drugs from entering.
The nanoghost’s cargo is a microRNA (miR), a stretch of genetic material that fine-tunes genetic messages by blocking the conversion of genes into proteins. First applied by NYU researchers to metastatic melanoma, miR-124a, in particular, blocks the expression of cancer- promoting genes. The joint team’s experiments will seek to determine the feasibility of encapsulating miR- 124a in the nanoghost, and study how the vehicle reaches its target in mice that carry the disease.
“Our studies should provide important information on nanoghosts’ general value as drug and gene carriers to the brain, and create potential for new treatment approaches against brain tumors and metastases,” said Prof. Marcelle Machluf, head of the Laboratory for Cancer Drug Delivery & Cell Based Technologies at the Technion and co-inventor of the nanoghost with her colleagues there.
“The difficulty of delivering agents to the brain represents a major impediment to improving outcomes in patients suffering from brain tumors,” she said.
“Our state-of-the-art nanovehicle promises safer, simpler and more clinically relevant treatments than existing vehicles, which are comprised of polymers or synthetic vesicles which largely lack the ability to enter the brain and to target evolving and changing pathologies.”
“It is much harder to secure funding for this type of highrisk, high-reward research,” said Associate Prof. Eva Hernando- Monge of the pathology department at NYU Langone. Hernando-Monge is also a member of the Perlmutter Cancer Center and the leader of the NYU team that first identified miR-124 as a suppressor of the growth of brain metastases. “The Perlmutters’ generous gift gives us the ability to be bold,” she said.
Like the stem cells they are based on, nanoghosts are invisible to the immune system, which means they could potentially be made from donated stem cells, expanded to large numbers in the lab, and not just from the patient’s own supply. In the future, this could enable the stockpiling of nanoghost treatments used off the shelf without fear of immune reactions to treatments based on “foreign” cells.
The second joint project will investigate whether an enzyme called heparanase can be used to diagnose and treat mesothelioma, a rare cancer that develops in the mesothelium, the protective lining of the lungs and other internal organs of the body.
Malignant pleural mesothelioma (MPM), the most common form of the disease, often occurs after exposure to asbestos and is resistant to most therapies.
Heparanase was first identified as a treatment target in 2004 by a team led by Prof. Israel Vlodavsky, one of the project’s co-investigators at the Technion’s Rappaport Faculty of Medicine. Past studies found that patients with high levels of this enzyme in their tumors have lower survival rates after surgery and that related tumors in mice respond to treatment with heparanase-inhibiting compounds.
The enzyme breaks up molecular chains of heparan sulfate, a building block of the scaffolds that give organs shape and support. Cancer cells use the enzyme to break down tissue barriers around a growing tumor, providing new pathways for the cancer to spread and for the building of blood vessels that supply tumors. In addition, breaking up extracellular matrices releases pro-growth proteins stored there to further drive disease. Furthermore, the joint team has developed the novel theory that heparanase secreted by tumor cells primes local micro-environments in a “vicious” cycle where inflammation and tumor growth drive each other.
The co-investigators at NYU Langone – led by thoracic surgeon Prof. Harvey Pass, will use tissue samples from its thoracic oncology archives to validate Vlodavsky’s findings in the hope of eventually evaluating the treatment potential of heparanase-inhibiting compounds in mesothelioma clinical trials.
Pass has been collecting tissue samples from his surgical patients since 1989, when he was head of thoracic oncology at the US National Cancer Institute (NCI). The collection now houses frozen specimens from more than 350 mesothelioma patients.
“This project, supported by the Perlmutters, enables us to collaborate with one of the world’s leading experts on the role of heparanase in cancer and is crucial in developing new strategies,” Pass said.
“We hope that these experiments can be translated into applications for ongoing funding from the NCI and enable Phase I trials with new therapeutics that influence heparanase pathways.”
“Our collaboration represents the first attempt to focus on heparanase as a major risk factor in mesothelioma and a valid target for the development of heparanase- inhibiting drugs,” Vlodavsky concluded. “In fact, applying a potent inhibitor of the heparanase enzyme we have already demonstrated a most prominent inhibition of tumor progression in mouse models of human mesothelioma, resulting in a pronounced extension of mouse survival.
This joint effort provides an opportunity to make important strides in both our fundamental understanding of mesothelioma and in translating this knowledge into therapeutics.”
Drug-carrying, stem-cell “nanoghosts” will be used in the project, financed by noted American-Jewish philanthropists and NYU Langone trustees Laura and Isaac Perlmutter. The first $3 million of the Perlmutters’ $9 million donation to the two institutions is earmarked to finance six joint research projects.
Co-investigators on each project will receive a twoyear, $500,000 grant – $250,000 for each site. The remaining $6 million is designated to establish a stateof- the-art research facility on the Technion campus in Haifa to support these and other research projects, primarily in the emerging field of cancer metabolomics, the systematic study of the unique chemical fingerprints that cellular processes leave behind. These processes are both affected by, and can influence, a variety of human diseases, including cancer.
NYU Langone and its Perlmutter Cancer Center – which the Perlmutters named in 2014 with a separate gift of more than $50 million – and the Technion established the new partnership last year to advance global collaboration in cancer research and therapeutics.
The joint program is positioned to attract additional support from institutions and individuals dedicated to eradicating cancer through focused and efficient research, the two institutions declared.