Proteome-Based Personalized Anti-Tumor Therapy

Our research team has focused its efforts on the application of the adult personalised therapy for neurooncology. This work resulted in the development of the individually tailored proteome-based anti-tumor cell preparations (PATCP) and systems with preset characteristics to be used in the complex therapy of the glial tumor and metastases of the brain the lung and breast cancer. For seven years we have been studying the personalised and molecular mechanisms of migration, homing, cell adhesion and pathotropism of adult cells to cancer cells in vitro and in vivo. We performed a comparative proteomic mapping of the proteins and a whole transcriptome profiling of the gene expression (WPPGE) of neural cells (СD 133+), which have been isolated from the olfactory sheath of the nose of a cancer patient, mobilized autologous hematopoietic (СD34+) cells and cancer (СD 133+) cells (Ccells), which have been isolated from the glial tumors of the brain (U87 and U251 glioblastoma multiforme lines) of the humans and animals (C6 rat glioma line), as well as the bioinformational processing and mathematical modeling of the obtained data. We detected global structural proteomic and transcriptomic differences of the studied adult cells and established the evidence that helped develop a novel platform of the personalized cytoregulatory effect on the reproductive and proliferative functions of the tumor cells by the specifically determined secretome of autologous cells with modified WPPGE.

1. We have proven in the experiment that the patient’s cells always reach the tumor in the brain, find the cancer cells (CCs) an Ccells, adhere to them and affect them according to the bystander effect.
2. Low efficiency of the anti-tumor regulatory and controlling effect of the cells on the CCs and Ccells is conditioned by the systemic mechanisms of speciation in the carcinogenesis that can be overcome by the specifically modified effector features of these cells based on the results of WPPGE.
3. We have demonstrated that from 30 to 60 % of the species-specific proteins can be mapped in the Ccells proteome, and their bioinformation analysis help detect the intrapersonalised pathways of signal transduction (ICPST) that have not been involved into the carcinogenic neoplastic transformation and remain accessible for targeted regulator effects.
4. The proliferative and reproductive functions of the tumor’s Ccells can be managed and controlled affecting known membrane target proteins of these ICPSTs in the Ccells.
5. The available databases of the protein-protein interactions permit detection of the main ligand proteins that are able to activate the membrane target proteins of the ICPSTs in the Ccells and manage the effector functions of the Ccells.
6. Use of this chemical induction helps modify the transcriptome profiles of the patient’s cells in specific direction avoiding gene engineering and develop the cell preparation from the autologous cells that express the necessary regulatory ligand proteins.
7. We developed a special software for the search of perturbagens (chemical agents and microRNAs) in the Affymetrix databases. The perturbagens are able to modify the WPPGE to induce specific properties under certain conditions and exposition time.

We demonstrated that the cell systems with modified WPPGE effectively suppress reproductive and proliferative properties of the CCs and Ccells of the brain tumor in the experiment in the rat models of brain tumors and confirmed the efficiency of the proposed cytoregulatory therapy. We showed the role and place of the proposed cytoregulatory method of the anti-tumor treatment in the complex conventional and immune therapies of the brain tumors. We proposed a new paradigm of the systemic proteome-based anti-tumor therapy that aims to transfer the acute and fatal malignant process into chronic non-lethal disease by the control of the number of the CCs and regulation of the Ccells. Currently, the technology is protected by the Russian patent application; the Scientific Boards an Ethics Committees of the Russian Cancer Center of the Russian Academy of Science and Federal Medical-Biological Agency approved the clinical trials. The project is registered at www.clinicaltrial.gov ( NCT01782287 for Proteome-based Immunotherapy of Lung Cancer Brain Metastases http://clinicaltrials.gov/ct2/show/NCT01782287?term=NCT01782287&rank=1, NCT01782274 for Proteome –based Immunotherapy of Brain Metastases from Breast Cancer http://clinicaltrials.gov/ct2/results?term =NCT01782274+&Search=Search NCT01759810 for Proteome-based Personalized Immunotherapy of Glioblastoma, http://clinicaltrials.gov/ct2/results?term= NCT01759810+&Search=Search).

Provisional results of the proteome-based Therapy of different types of cancer

Table 1.

Distribution of the cancer cases at 3-4 stage into the control group and trial groups that receive precision IT

Table 2.

Distribution of the control group cancer cases at 3-4 stage by age and sex

Table 3.

Distribution of the trial group cancer cases at 3-4 stage by age and sex

Table 4

Distribution of the control group patients with metastatic damage of the brain by the degree of compensation as measured by Karnofsky/ ECOG performance scales

Table 5

Distribution of the trial group patients with metastatic damage of the brain by the degree of compensation as measured by Karnofsky/ ECOG performance scales

Table 6.

The distribution of the 3-4 stage cancer cases depending on the immunotherapy strategy

Table 7.

The efficiency of the antitumor IT in various types of cancers, stage 3-4

Table 8.

The life span of the breast and lung cancer patients with the metastases to the brain and the patients with glioblastoma multiforme in the trial groups

Table 9

Safety of the precision immunotherapy of cancer and other malignant neoplasms