Periodic Reporting for period 2 - BaCTher (Bacteria for Cancer Therapy)
Periodo di rendicontazione: 2016-11-01 al 2017-10-31
After the advent of radiation therapy and chemotherapy, Bacteria-mediated cancer therapy introduced in the late 19th century by William B. Coley, with his Coley’s toxins Streptococcus pyogenes to treat inoperable sarcomas, gradually disappeared from medical practice. However, recent progress in the fields of immunology and biotechnology has revived the mechanism underlying the activity of Coley’s toxin, meaning that bacteria have returned to the agenda of those undertaking cancer researches. In the past 20 years, bacterial cancer therapy has again become a hot topic, and various kinds of bacteria have been the subject of preclinical and clinical research.
The specific hypothesis behind the project was that an attenuated Salmonella enterica serovar Typhimurium (STMΔznuABC) is able to influence the tumor microenvironment (TME) reprogramming or re-educating the immune response, and inducing a shift from protumorigenic inflammation to anticancer immunity, which results in a tumor growth control. Therefore, BaCTher project has been conceived to investigate a novel strategy to expand the current arsenal of anti-tumor weapons in order to overcome the intrinsic limitations of standard anti-cancer therapies.
During the first year of the project we demonstrated that STMΔznuABC is able to reach the tumor zone and to specifically localize around tumor cells; we identified specific involvement of immune cells demonstrating that STMΔznuABC was able to recall more immune cells in the TME, in both primary and secondary metastatic tumor of treated mice compared to the untreated mice; and the ability of STMΔznuABC to induce the modification of the TME and the systemic immune system.
We demonstrated, during this second part, that STMΔznuABC has anti-tumor activity not only in syngeneic breast cancer mice model, as demonstrated during the first year of the project, but also on genetically engineered breast cancer-prone female mice and chemically fibrosarcoma cancer mouse model. STMΔznuABC, indeed, is able to reach the tumor zones, tumors of different embryological origin, significantly reduce the tumor growth and significantly increase the survival of the tumor-bearing mice compared to the untreated group.
The specific hypothesis behind the project was that an attenuated Salmonella enterica serovar Typhimurium (STMΔznuABC) is able to influence the tumor microenvironment (TME) reprogramming or re-educating the immune response, and inducing a shift from protumorigenic inflammation to anticancer immunity, which results in a tumor growth control. Therefore, BaCTher project has been conceived to investigate a novel strategy to expand the current arsenal of anti-tumor weapons in order to overcome the intrinsic limitations of standard anti-cancer therapies.
During the first year of the project we demonstrated that STMΔznuABC is able to reach the tumor zone and to specifically localize around tumor cells; we identified specific involvement of immune cells demonstrating that STMΔznuABC was able to recall more immune cells in the TME, in both primary and secondary metastatic tumor of treated mice compared to the untreated mice; and the ability of STMΔznuABC to induce the modification of the TME and the systemic immune system.
We demonstrated, during this second part, that STMΔznuABC has anti-tumor activity not only in syngeneic breast cancer mice model, as demonstrated during the first year of the project, but also on genetically engineered breast cancer-prone female mice and chemically fibrosarcoma cancer mouse model. STMΔznuABC, indeed, is able to reach the tumor zones, tumors of different embryological origin, significantly reduce the tumor growth and significantly increase the survival of the tumor-bearing mice compared to the untreated group.
The second part of the project was the return period at the Istituto Superiore di Sanità (ISS), performed in the lab directed by Dr. Paolo Pasquali, in which new results were made on the specific aim.
The general objective of BaCTher project was the experimental demonstration and the understanding of the ability of STMΔznuABC to reach the tumor zone and influence the TME reprogramming or re-educating the immune response, inducing a shift from protumorigenic inflammation to anticancer immunity, which results in a tumor growth control.
In this context, the specific aim of the second part of the study was:
• to validate the results obtained in the preliminary studies using alternative in vivo models.
In this context, two different mouse models have been set up to validate the capability of STMΔznuABC to control cancer growth and improve the knowledge on its potential therapeutic:
i) Genetically engineered, cancer-prone female mice that more closely mimic several features of human cancer. These homozygous MMTV-PyMT females develop palpable mammary tumors on all fourth pair of mammary fat pad of the mice, thoracic and inguinal. These mice have high penetrance and early onset of mammary cancer compared to other mammary tumor models.
ii) Methylcholanthrene (3-MCA)-induced chemical tumors in female Balb/c mice, which develop local fibrosarcomas, a tumor of different embryological origin.
Also in this case, the evaluation of tumor progression, invasion and intracellular replication of STMΔznuABC in tumor tissues, survival curves and tumor reduction were performed.
The results indicated that STMΔznuABC greatly reaches the tumor zone and significantly reduces the tumor growth in both tumor mouse models.
The general objective of BaCTher project was the experimental demonstration and the understanding of the ability of STMΔznuABC to reach the tumor zone and influence the TME reprogramming or re-educating the immune response, inducing a shift from protumorigenic inflammation to anticancer immunity, which results in a tumor growth control.
In this context, the specific aim of the second part of the study was:
• to validate the results obtained in the preliminary studies using alternative in vivo models.
In this context, two different mouse models have been set up to validate the capability of STMΔznuABC to control cancer growth and improve the knowledge on its potential therapeutic:
i) Genetically engineered, cancer-prone female mice that more closely mimic several features of human cancer. These homozygous MMTV-PyMT females develop palpable mammary tumors on all fourth pair of mammary fat pad of the mice, thoracic and inguinal. These mice have high penetrance and early onset of mammary cancer compared to other mammary tumor models.
ii) Methylcholanthrene (3-MCA)-induced chemical tumors in female Balb/c mice, which develop local fibrosarcomas, a tumor of different embryological origin.
Also in this case, the evaluation of tumor progression, invasion and intracellular replication of STMΔznuABC in tumor tissues, survival curves and tumor reduction were performed.
The results indicated that STMΔznuABC greatly reaches the tumor zone and significantly reduces the tumor growth in both tumor mouse models.
The second year of BaCTher was dedicated to set up the in vivo models for studying the ability of STMΔznuABC to influence cancer growth, survival and immunity of alternative in vivo tumors bearing-mice models, genetically engineered and chemical-induced tumors, consolidating the knowledge and information previously generated.
The results obtained so far confirmed and deeply strengthened the knowledge obtained during the first part of the project and expanded the potential application and exploitation of STMΔznuABC within the therapeutic range of weapons. Moreover, this new information enlarged the general knowledge on tumor microenvironment and the alternative therapeutic strategies.
Furthermore, the most important impact of BaCTher was characterized by the equipment, in term of knowledge and skills, provided from this project to the ER with a creative mind, an entrepreneurial outlook and innovation skills that is matching with the needs of the labour market and the research institutes. This experience strength her skills in grant and patent applications, management, supervising and monitoring, and exploitation of research results, greatly improving her CV.
The results obtained so far confirmed and deeply strengthened the knowledge obtained during the first part of the project and expanded the potential application and exploitation of STMΔznuABC within the therapeutic range of weapons. Moreover, this new information enlarged the general knowledge on tumor microenvironment and the alternative therapeutic strategies.
Furthermore, the most important impact of BaCTher was characterized by the equipment, in term of knowledge and skills, provided from this project to the ER with a creative mind, an entrepreneurial outlook and innovation skills that is matching with the needs of the labour market and the research institutes. This experience strength her skills in grant and patent applications, management, supervising and monitoring, and exploitation of research results, greatly improving her CV.