TY  - JOUR
A1  - Rasche, Leo
A1  - Kortüm, K. Martin
A1  - Raab, Marc S.
A1  - Weinhold, Niels
T1  - The impact of tumor heterogeneity on diagnostics and novel therapeutic strategies in multiple myeloma
JF  - International Journal of Molecular Sciences
N2  - Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted.
KW  - multiple myeloma
KW  - spatial heterogeneity
KW  - risk stratification
KW  - minimal residual disease
KW  - targeted therapy
KW  - clinical imaging
KW  - immunotherapy
KW  - daratumumab
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285402
SN  - 1422-0067
VL  - 20
IS  - 5
ER  - 
TY  - JOUR
A1  - Munawar, Umair
A1  - Zhou, Xiang
A1  - Prommersberger, Sabrina
A1  - Nerreter, Silvia
A1  - Vogt, Cornelia
A1  - Steinhardt, Maximilian J.
A1  - Truger, Marietta
A1  - Mersi, Julia
A1  - Teufel, Eva
A1  - Han, Seungbin
A1  - Haertle, Larissa
A1  - Banholzer, Nicole
A1  - Eiring, Patrick
A1  - Danhof, Sophia
A1  - Navarro-Aguadero, Miguel Angel
A1  - Fernandez-Martin, Adrian
A1  - Ortiz-Ruiz, Alejandra
A1  - Barrio, Santiago
A1  - Gallardo, Miguel
A1  - Valeri, Antonio
A1  - Castellano, Eva
A1  - Raab, Peter
A1  - Rudert, Maximilian
A1  - Haferlach, Claudia
A1  - Sauer, Markus
A1  - Hudecek, Michael
A1  - Martinez-Lopez, J.
A1  - Waldschmidt, Johannes
A1  - Einsele, Hermann
A1  - Rasche, Leo
A1  - Kortüm, K. Martin
T1  - Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma
JF  - Communications Biology
N2  - The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.
KW  - immunotherapy
KW  - translational research
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357609
VL  - 6
ER  -