Periodic Reporting for period 3 - Tumor microbiome (The tumor microbial communities: Characterization, effects and translational opportunities)
Reporting period: 2022-05-01 to 2023-10-31
Bacteria are part of the human body and their total number may exceed the number of human cells. While traditionally, bacteria were mostly described on the skin as well as in the gastro-intestinal track, over the last few years it has been suggested that bacteria can also be found in human tumors. For example – our group demonstrated that bacteria can be found in human pancreatic tumors and may contribute to drug resistance. The bacteria were shown to ‘hide’ inside cancer cells, and protect the cancer cells from the commonly used anti-cancer drug gemcitabine, by degrading and inactivating the drug.
In the current project, we suggested to greatly increase the characterization of the tumor microbiome, study its effects on tumor biology and capitalize on the findings to introduce novel treatment modalities. We hypothesize that bacteria in tumors have a yet unknown influence of many aspects of tumor biology and that better characterization of these effects would thus lead to completely new treatment options.
In the current project, we suggested to greatly increase the characterization of the tumor microbiome, study its effects on tumor biology and capitalize on the findings to introduce novel treatment modalities. We hypothesize that bacteria in tumors have a yet unknown influence of many aspects of tumor biology and that better characterization of these effects would thus lead to completely new treatment options.
During the first half of the project, we were able to characterize the human tumor microbiome in an unprecedented way. We explored a cohort of more than 1,500 human tumors originating from eight different solid tumor types. We showed that bacteria can be found in all of these tumor types and that each tumor type has a different signature of bacteria. We found that most of the bacteria in tumors are intra-cellular, mostly in cancer and immune cells, and also found some bacteria that are correlated with response to immunotherapy. By studying the functions of bacteria in specific tumor types we could uncover some aspects of the tumor type-specific bacterial signatures. For example, we showed that in lung tumors from smokers there is an enrichment for bacteria that can degrade nicotine as compared to lung tumors from non-smokers. We could also culture live bacteria from human tumors and are now studying these bacteria and their effects in mice cancer models.
We have done a few screens looking for the effect of bacteria on response to anti-cancer drugs and decided to follow an interesting finding in which bacteria that are present in lung cancer can reduce the sensitivity of lung cancer cells to commonly used anti-cancer treatment. We are now working on dissecting the molecular mechanism by which the bacteria mediate this effect.
We have also been using bacteria as a novel anti-cancer drug. We found that some bacteria home preferentially to tumors upon their intravenous (IV) injection. We thus use attenuated bacteria that we genetically engineer to deliver payloads to the tumor. We show that the presence of the bacteria in the tumors and the specific payloads that we add to them can activate the immune response and lead to tumor retraction in multiple mice cancer models.
We have done a few screens looking for the effect of bacteria on response to anti-cancer drugs and decided to follow an interesting finding in which bacteria that are present in lung cancer can reduce the sensitivity of lung cancer cells to commonly used anti-cancer treatment. We are now working on dissecting the molecular mechanism by which the bacteria mediate this effect.
We have also been using bacteria as a novel anti-cancer drug. We found that some bacteria home preferentially to tumors upon their intravenous (IV) injection. We thus use attenuated bacteria that we genetically engineer to deliver payloads to the tumor. We show that the presence of the bacteria in the tumors and the specific payloads that we add to them can activate the immune response and lead to tumor retraction in multiple mice cancer models.
In addition to the study of intra-tumor bacteria we also explored the presence of intra-tumor fungi. We recently completed a thorough study in which we characterized tumors from seven different cancer types for the presence of fungi using both sequencing based methods as well as immunostaining. We found fungi to be present in all tumor types though in a lower load as compared to bacteria. We found interesting correlations between the presence of specific fungi and clinical data as well as fascinating connections between specific fungi and bacteria.
Most of the tumors that we studied thus far were obtained pre-treatment. To study the effect of treatments on the microbial community in tumors we are now studying cohorts from breast cancer patients in which the tumors were samples both pre and post treatment. We were able to identify bacteria that are highly enriched after therapy and are currently validating these results is additional cohorts as well as trying to understand why specific bacteria are enriched post treatment and the clinical importance of this observation.
We have previously demonstrated that specific bacteria can be found in human pancreatic tumors and can degrade the anti-cancer drug gemcitabine and thus confer drug resistance. Now, using advanced technology, which allows us to grow human tumors in the lab, we are exploring how addition to antibiotics can synergize with gemcitabine. These experiments, if successful, would hopefully lead to clinical trials in pancreatic cancer patients.
We are also putting a lot of effort is engineering bacteria that we deliver to tumor to express more and better payloads, in order to optimize their effects. We are testing the effects of our bacteria on mice tumor models and explore not only the effect on tumor size but also the effect of the mice systemic immune profile and on the tumor immune landscape. Here as well, we hope to be able to translate our findings into clinical trial in human patients.
Most of the tumors that we studied thus far were obtained pre-treatment. To study the effect of treatments on the microbial community in tumors we are now studying cohorts from breast cancer patients in which the tumors were samples both pre and post treatment. We were able to identify bacteria that are highly enriched after therapy and are currently validating these results is additional cohorts as well as trying to understand why specific bacteria are enriched post treatment and the clinical importance of this observation.
We have previously demonstrated that specific bacteria can be found in human pancreatic tumors and can degrade the anti-cancer drug gemcitabine and thus confer drug resistance. Now, using advanced technology, which allows us to grow human tumors in the lab, we are exploring how addition to antibiotics can synergize with gemcitabine. These experiments, if successful, would hopefully lead to clinical trials in pancreatic cancer patients.
We are also putting a lot of effort is engineering bacteria that we deliver to tumor to express more and better payloads, in order to optimize their effects. We are testing the effects of our bacteria on mice tumor models and explore not only the effect on tumor size but also the effect of the mice systemic immune profile and on the tumor immune landscape. Here as well, we hope to be able to translate our findings into clinical trial in human patients.