Research projects
Our research projects - Our preclinical in-vivo research model
Importance of HER receptor tyrosine kinases for the treatment of breast cancer
Functional and quantitative studies of HER receptor tyrosine kinases (RTKs) are an essential component of the working group. ("HER" = "Human Epidermal Growth Factor Receptor Related") These membrane-expressed receptors regulate development and differentiation processes in healthy organisms. In tumor pathology, they play a role in carcinogenesis, tumor progression, and metastasis. HER-RTKs are highly posttranslationally regulated molecules that influence cell proliferation and growth, migration and adhesion, as well as cell survival and death at the cellular level. However, HER-RTK activity has different effects in the respective breast cancer types and does not influence disease progression (prognosis) or treatment response (prediction) in the same way.
The four related receptors HER1 (= EGFR), HER2, HER3, and HER4 are characterized by a great potential for molecular interactions with each other, but also with other membrane-bound molecules (lateral or horizontal signal transduction via homo- and heterodimerization), thereby triggering numerous intracellular signaling pathways (vertical signal transduction). They thus represent a complex, functional system that can be used for tumor therapy (antigen-specific therapies). The diverse interactions of the HER receptors, not only with each other but also with other receptor and signaling systems, enable diverse approaches for therapy optimization and the development of new treatment strategies.
Neoadjuvant tumor irradiation in combination with targeted immune checkpoint therapy
The majority of breast cancers are poorly immunogenic. Accordingly, many patients have virtually no natural defense against the tumor. In other breast cancers, immunological tumor defense is inhibited by the tumor cell-associated expression of so-called immune checkpoint molecules, such as PD-L1. There is considerable evidence that radiation therapy can stimulate the body's own immune defense or increase the effectiveness of immune checkpoint therapy (anti-PD-L1). However, to date, radiation therapy of the tumor bed has typically been performed in the adjuvant setting, i.e., after surgical removal of the primary tumor.
With our project work, we intend to evaluate, in a preclinical approach, conditions for irradiation of the primary tumor prior to its excision (i.e., preoperatively or neoadjuvantly), which lead to an increased release of tumor-specific neoantigens and thus to the stimulation of immune defense. Tumor irradiation is thus likely to be equivalent to an autologous vaccination with patient-specific tumor antigens and efficiently stimulate antigen-specific (e.g., cytotoxic) immune cells. At the same time, an "immune memory" (memory cells) is induced, which would ensure the body's long-term immune defense. Furthermore, studies have shown that irradiation can lead to increased PD-L1 expression directly and indirectly (due to immune cell activation). Therefore, it can be expected that primary tumor irradiation will also enhance the efficacy of externally administered downstream immunotherapy (anti-PD-L1). (In addition, primary tumor irradiation as an alternative to neoadjuvant, cytotoxic treatment could contribute to therapy de-escalation.) The therapy studies will be conducted in the "humanized tumor mouse model" (HTM), which is characterized by human tumor growth in the presence of a, functional human immune system (see below).
Endocrine and anti-CDK4/6 therapy of estrogen receptor-positive breast cancer depending on the HER4 receptor
The most common form of breast cancer is hormone receptor-positive breast cancer, in which tumor growth is regulated by estrogen. Affected patients often receive long-term treatment with tamoxifen, a substance that inhibits the activity of the estrogen receptor and is thus intended to halt tumor growth. However, the growth of the malignant cells is often not sufficiently slowed, and resistance to this treatment develops. Therefore, it is important to find biological markers that can be used, on the one hand, to predict the expected response to a given therapy and, on the other hand, can themselves be used as therapeutic targets. This could improve the treatment success for each individual patient.
The research group has succeeded in identifying a marker that appears to have a significant impact on hormone therapy with tamoxifen. If this marker, the so-called HER4 receptor, can be detected on the tumor cells, treatment with tamoxifen is far less effective than if the tumor cells lack this surface molecule. Thus, in case of HER4-positive luminal breast cancer one could switch to a potentially more effective, alternative therapy or therapeutically target the HER4 receptor itself. The cellular and molecular biological HER4-dependent mechanisms responsible for inadequate treatment success with tamoxifen are now being investigated in more detail.
Mdm2: Key molecule for response to CDK4/6 inhibition and complementary therapy target
The ubiquitin ligase mdm2 (mouse double minute 2 homolog) is crucial for the regulation of p53. Overexpression or hyperactivity of mdm2 leads to inactivation of p53 and thus to uncontrolled cell proliferation, inadequate repair of DNA damage, and the inability of (malignant) cells to undergo programmed cell death. Downregulation of mdm2 appears to be essential for the response to CDK4/6 inhibitors (e.g., abemaciclib). Conversely, a stable mdm2 protein apparently marks an insufficient therapeutic response or even treatment resistance. Complementary therapeutic targeting of mdm2 could improve the response to CDK4/6 inhibitors and contribute to overcoming resistance. This may be best achieved through the use of so-called PROTAC (PRoteolysis TArgeting Chimeras) molecules (instead of mdm2 inhibitors), which ensure the specific degradation of target molecules. We are evaluating such molecule-specific combination approaches to increase treatment efficacy using suitable therapy models.
Immune checkpoint profiling of T lymphocytes: Multiple checkpoints and their relevance for immunotherapy of breast cancer
In addition to established therapeutic modalities such as chemotherapy or radiation, immunotherapies are increasingly being used in the treatment of cancer. Although significant progress has been made in this field, innovative and, above all, individualized strategies for breast cancer are lacking, which highlights the urgency of research in this area. Compared to other malignancies, breast cancer is generally relatively poorly immunogenic, which makes treatment with immunotherapies difficult. The approval of checkpoint inhibitors therefore represented a major breakthrough for patients with triple-negative breast cancer (TNBC). However, not all TNBC patients respond to these checkpoint inhibitors, and alternative immunological approaches are lacking. The other subtypes have so far shown only very little or no response to the medication approved for TNBC patients. In addition to blocking the PD-1/PD-L1 axis with specific antibodies such as atezolizumab or pembrolizumab, the inhibition of other checkpoints such as LAG-3, VISTA, TIGIT, or TIM-3 on T lymphocytes is being discussed. Therefore, the checkpoint profile on T lymphocytes in various breast cancer subtypes (ER+/HER2-, ER+/HER2+ , ER-/HER2+, ER-/HER2-) will be analyzed. Since patients can develop serious resistance to checkpoint inhibitors during therapy, the effect of the already approved anti-PD-1/anti-PD-L1 therapy on the expression and possible regulation of other checkpoint molecules will be analyzed. These studies are intended to contribute to a better understanding of tumor immunological mechanisms that may be important during checkpoint therapy and open up possibilities for individually tailored, complementary treatments.
The Humanized Tumor Mouse (HTM) - a preclinical in-vivo model for therapeutic studies
Many tumor therapy approaches demonstrate significant efficacy in pure mouse models, but this efficacy cannot be confirmed in subsequent clinical trials in patients. As a result, only a fraction of newly developed drugs or therapeutic approaches receive approval for clinical use. New immunotherapies, in particular, demonstrate great clinical potential, but the functional differences in the immune system between mice and humans often prevent the findings obtained using a pure mouse model from being directly translated.
Therefore, in 2011, we developed a "human-like" mouse model that develops both a human immune system and exhibits human tumor growth, thus allowing for better transferability and testing of new therapeutic approaches. We have extensively characterized the mouse model and have since used it for various therapy studies. The translational in-vivo model allows for the early evaluation of undesirable or even dangerous side effects. Using humanized tumor mice (HTM), for example, we have been able to investigate the therapeutic effects of IL-15, CX3CL1, and tumor-specific antibodies on human tumors under the influence of human immune cell activity. We can use this model to demonstrate new diagnostic procedures, such as the use of contrast agents in ultrasound-based tumor diagnostics. We are currently using the HTM model, for example, to evaluate neoadjuvant tumor radiation in combination with immunotherapy, as well as to analyze endocrine and anti-CDK4/6 treatments depending on the HER4 receptor (see above). The immune checkpoint profiling is also based on the HTM.
Since 2011, we have published over ten therapy studies and a variety of immune effects under therapeutic pressure based on HTM.