Periodic Reporting for period 4 - ELIMINATE (Development of strategies to eliminate cancer cells from the bone marrow)
Reporting period: 2022-01-01 to 2024-01-31
There is an utmost medical need to develop strategies for the elimination of cancer cells from the bone marrow (BM) because it represents the prime location in which cancer cells persist. Alarmingly, the mortality of early-stage breast cancer patients is twice as high when disseminated tumor cells (DTC) are present in their BM compared to patients without DTC. This means that approximately 50.000 women with curable breast cancer die per year in the EU because of relapse attributed to DTC. Similarly, in leukemia established treatments are unable to completely eradicate the neoplastic cells in many cases. This persistence of malignant cells is termed minimal residual disease (MRD). MRD represents a major health problem for millions of patients with solid tumors and leukemia alike because it mostly precludes cure. In light of the failure of conventional therapies it is therefore of paramount importance to develop novel strategies to eradicate cancer cells from the BM.
Hematologic and solid tumor cells abuse the BM as “safe haven” to survive anti-cancer treatments. Although these cells are of different tissue origin they use partially overlapping mechanisms to ensure their survival in the BM. The majority of existing literature refers to similar mechanisms between both malignant cell types regarding interaction with important cell populations implicated in bone remodelling. In contrast, we have very little knowledge whether solid and hematologic cancer cells differ in their interaction with immune cells in the BM. Gaining these insights is crucial for developing therapeutic approaches to enable the immune system to combat solid vs. hematologic cancer cells in the BM.
Very little knowledge exists about anti-cancer immune responses in the BM of cancer patients and the interaction between immune cells and immune-modulatory BM stroma cells. Furthermore a relevant knowledge gap is whether immune-checkpoint blockers can elicit anti-cancer immune responses in the BM. The challenge is to understand the specific immune microenvironment in the BM by integrating information from the hematology, oncology and basic research fields. Thus, this proposal aims to develop multidisciplinary bench-to-bedside and reverse approaches that will enable a comprehensive understanding of the immune microenvironment and novel strategies to harness the immune system to combat cancer in the BM will emerge.
Hematologic and solid tumor cells abuse the BM as “safe haven” to survive anti-cancer treatments. Although these cells are of different tissue origin they use partially overlapping mechanisms to ensure their survival in the BM. The majority of existing literature refers to similar mechanisms between both malignant cell types regarding interaction with important cell populations implicated in bone remodelling. In contrast, we have very little knowledge whether solid and hematologic cancer cells differ in their interaction with immune cells in the BM. Gaining these insights is crucial for developing therapeutic approaches to enable the immune system to combat solid vs. hematologic cancer cells in the BM.
Very little knowledge exists about anti-cancer immune responses in the BM of cancer patients and the interaction between immune cells and immune-modulatory BM stroma cells. Furthermore a relevant knowledge gap is whether immune-checkpoint blockers can elicit anti-cancer immune responses in the BM. The challenge is to understand the specific immune microenvironment in the BM by integrating information from the hematology, oncology and basic research fields. Thus, this proposal aims to develop multidisciplinary bench-to-bedside and reverse approaches that will enable a comprehensive understanding of the immune microenvironment and novel strategies to harness the immune system to combat cancer in the BM will emerge.
We compared the stroma transcriptome of AML patients to healthy donors and established a co-culture system of primary MSC from AML patients and human T cells. We identified three potential novel targets with the potential to decrease stroma-mediated immunosuppression. In addition we were able to recruit patients with breast cancer to participate in the ELIMINATE study and analysis their transcriptome in comparison to AML patients. We could identify a MSC-derived factor contributing to immunosuppression in the BM of AML patients and elucidate its role via co-cultures and will utilize different newly established as well as well studied models to perform in vivo validations of the alleviation of BM stroma-elicited immunosuppression by their genetic and pharmacologic targeting. After completion of stroma transcriptomic analyses of BC patients additional candidates were evaluated. We obtained interesting findings when comparing the transcriptome of AML patients to that of breast cancer patients and healthy donors by pathway analyses. We identified allograft rejection as the main differentially expressed pathway compared to healthy samples both in AML and in breast cancer, confirming the ELIMINATE central hypothesis.
By studying human AML samples we identified three potential druggable stroma-related targets whose inhibition will be subsequently tested in vitro and in vivo with respect to their potential to augment anti-tumor responses in the bone marrow. In comparison, we will investigated the bone marrow stroma of patients with breast- and lung cancer with the aim to understand whether similar druggable pathways are altered in the bone marrow microenvironment between solid and hematologic malignancies. This insight is important for the development of personalized treatments. We are currently translatin our findings into a clinical trial specifically targeting malignant cells in the bone marrow niche.