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Anti-Tumor Vaccines Based on Heat Shock Proteins

#4009


Development of Individual Anti-Tumor Vaccines Based on Molecular Chaperones

Tech Area / Field

  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology

Status
8 Project completed

Registration date
22.01.2010

Completion date
17.01.2013

Senior Project Manager
Melnikov V G

Leading Institute
Pacific Institute of Bioorganic Chemistry, Russia, Primorsky reg., Vladivostok

Supporting institutes

  • Institute of Cytology, RAS, Russia, St Petersburg

Collaborators

  • Chiba University / Graduate School of Pharmaceutical Sciences, Japan, Chiba

Project summary

Cancer is a leading cause of people death worldwide independently of their sex, age and life quality. Many therapeutic strategies to fight cancer were established, which use low molecular-weight inhibitors of tumor growth, specific antibodies, apoptosis inducers, steroid compounds and vaccines. Despite the impressive success with some of the current approaches it becomes clear that the above drugs and many other pharmacological compounds possess essential side effects. Patients receiving such drugs are suffering from previously untypical, sometimes rather hard, illnesses like the immune disorders. So, the problems of cancer therapy and of timely and careful cancer drug application still remain the burning problems. In this relation, a new inpidual cancer vaccine based on chaperones, able to enhance immunogenicity of cancer antigens, appears to be of considerable promise.

The main goal of the project is to design anticancer vaccines based on: (1) chemical compounds able to enhance synthesis and to stimulate Hsp70 chaperone export from cancer cells and (2) the preparations of purified Hsp70. The joint studies are to test all the compounds and preparations obtained on models of oncological diseases.

The objectives of the project are: to screen the compounds from the collection of PIBOC with regard to possible Hsp70-inducing activity and to test the most active ones in animal cancer models. The project team from INC will develop the preparations of recombinant Hsp70 and measure their anti-cancer activities using the same oncological models. The priority of data that can be obtained for the project is undoubted and therefore the project will result in completion of Patent Applications.

The project proposed arises from current developments of cancer vaccines based on chaperons, including those based on Hsp70 protein or Hsp70 gene. The Hsp70 family proteins are able of recognizing newly synthesized or damaged by stress polypeptides and of correcting their structure or sending the incorrigible proteins to degradation in specific cellular machineries lysosomes and proteasomes. It is well established that among key biological properties of Hsp70 is its protective function that is assumed to be related to chaperone activity. This property is very important for normal cells however it may hamper the development of tools of cancer therapy suggested to kill tumor cells. Later it became clear that Hsp70 can be exported to a cancer cell surface and can present its peptides to antigen-presenting cells, thus activating both, the cellular and antibody immune response. It was also shown that chaperone can exit to extracellular matrix and activate the innate immunity.

The low-molecular weight compounds able to induce Hsp70 cellular synthesis and to export it to a cancer cell surface in complex with tumor antigens will be analyzed by the team from PIBOC in collaboration with the INC team. At this stage it is planned to screen the libraries of natural and synthetic compounds from the PIBOC collection. To date the most appropriate are the collections of: dammarane type triterpenes and the derived o-glycosides, which are the analogs of ginsenosides of Panax Ginseng roots isolated by C.A.Meyer; heterocyclic “marine natural alcaloids” and their analogs; natural and synthetic1,4-naphthoquinones and their O- and S-glycoside derivatives.

The following results are expected for the project:

  • Methodology to assay the intracellular and surface Hsp70 tumor chaperones.
  • Low-molecular compounds – the potential inducers of Hsp70 and the data of their analysis.
  • Protocols of screening for natural and synthetic compounds from PIBOC collection and of some other compounds for the ability of inducing Hsp70 synthesis and export to a tumor cell surface. The most potent stimulators will be selected.
  • Protocols of study of structure and bioactivities for the selected compounds.
  • Protocols of Hsp70 proteins purification from the bovine muscle and from E.coli biomass. Data of assay of the physicochemical properties and bioactivities for the proteins produced.
  • Protocols of the in vivo studies in animal models of anti-cancer activities of the Hsp70 preparations produced.

The results obtained for the project will be used in public health care and medicine.

Based on the data obtained for the project, the prototype of the vaccine based on low-molecular Hsp70 inducers or on the Hsp70 protein will be designed. We expect these vaccines to be applicable in therapy of different types of cancer. In case of success, the Patent Applications concerning the produced preparations and the methodology of the inpidual vaccine application will be prepared with possible out-licensing to interested companies.

The technical approaches will be:

  • the methods to select and characterize low-molecular compounds for possible Hsp70-inducing activities;
  • methods of chemistry and protein chemistry to analyze low- and high-molecular compounds;
  • immunochemical and biochemical methods for assaying the cellular and surface Hsp70 proteins, including enzyme immunoassay, shaperone test, assay with HSE-Luciferase as a reporter protein and some other assays;
  • the methods to test the Hsp70-inducers and purified Hsp70 proteins in CTL-system;
  • the polymerase chain reaction to analyze the expression of cancer cell Hsp70.


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