Working Group of Prof. Dr Kubuschok

• Manuela Meyer (PhD student)
• Pia Hofmann (PhD student)

• CUPISCO study: Initial results were presented at the European Society for Medical Oncology (ESMO) Congress. 
• PhD positions focusing on pathology and clinical parameters relating to CUP, as well as in the field of tumour immunology
• Prof. Kubuschok is a member of the Carcinoma of Uncertain Origin Working Group within the German Association for Medical Oncology (AIO) >> further information
• Dr. Wolfbauer Foundation Award for doctoral candidate Manuela Mayer for her poster on prognostic factors in the nonspecific CUP syndrome.

CUP syndrome: CUP syndrome (Cancer of Unknown Primary) is defined as a histologically confirmed malignancy with an unknown primary tumour following completion of the initial diagnostic work-up. Its aetiology and pathogenesis remain largely unclear. It is likely that the metastases have a growth advantage over the primary tumour. In some cases, the primary tumour and metastases are indistinguishable, e.g. in tumours of the liver and lung. On the other hand, a primary tumour may regress spontaneously. The stem cell theory of cancer also offers a possible explanation: during the asynchronous division of the malignantly transformed stem cell, daughter cells may arise which do not grow locally but are capable of metastasising and form metastases elsewhere if the microenvironment is favourable. Treatment options are limited, particularly for the group with a poor prognosis comprising adenoid and undifferentiated carcinomas of unclear origin. The aim of the research group is therefore to gain a better understanding of the risk factors and pathobiology of the disease. Based on these findings, new approaches to the diagnosis and treatment of the disease are to be developed.

Resistance mechanisms under checkpoint inhibitor therapy
The immune system plays a key role in defending against lung cancer. However, lung cancer cells are able to switch off the immune system via ‘switches’ (checkpoints) on the immune cells, thereby evading the immune response. Immunotherapy using antibodies against these checkpoints, which can reverse the suppression caused by tumour cells (so-called checkpoint antibodies or checkpoint inhibitors), has contributed to a significant improvement in treatment outcomes in recent years. Despite these successes, a proportion of patients with metastatic lung cancer do not respond to this therapy and continue to have a poor prognosis. In order to develop a successful therapy for these patients as well, our research group is investigating which resistance mechanisms lead to this and whether biomarkers can be identified that are suitable for better predicting response to checkpoint inhibitor therapy. A particular focus is on the investigation of the tumour microenvironment.

Aggressive lymphomas: B-cell receptors in various non-Hodgkin’s lymphomas bind to a specific target antigen with above-average frequency. Typically, this target antigen differs across various types of B-cell lymphoma; however, patients with the same type of lymphoma disproportionately often have lymphoma B-cell receptors that recognise the same target structure. This target structure may consist of either human proteins or foreign proteins, such as those from infectious agents. It is thought that these proteins contribute to the development of non-Hodgkin’s lymphomas through chronic stimulation of the B-cell receptors. This is the subject of ongoing research. Furthermore, the shared reactivity of the B-cell receptors in non-Hodgkin’s lymphomas against specific target structures could be utilised in future for new therapeutic approaches.

CUP syndrome

• Prognostic parameters (M. Meyer)
• New molecular targets (in collaboration with M. Esteller – Barcelona, Spain)

Tumour immunology

• Resistance mechanisms under checkpoint inhibitor therapy (P. Hofmann)

Aggressive lymphomas

• New molecular targets (in collaboration with L. Thurner, Saarland University Hospitals)
• MRD in ALL (in collaboration with O. Ottmann, Cardiff University, UK)

Pouyiourou M., Kraft B., Wohlfromm T., Stahl M., Kubuschok B., Löffler H., Hacker U., Hübner G., Westphalen C.B., Bitzer M., Ernst T., Schütt P., Hielscher T., Delorme S., Stenzinger A., Bochtler T., Krämer A.
Phase II study of nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary.
Nature Communications, 2023, in press.

Preuss KD, Pfreundschuh M., Weigert M., Fadle N., Regitz E., Kubuschok B.
Sumoylated HSP-90, a dominantly inherited risk factor for plasma cell dyscrasias.
J. Clin. Invest., 125(1): 316–23, 2015.

Neumann F, Pfreundschuh M, Preuss KD, Schormann C, Zwick C, Murawski N, Kubuschok B.
CD4+ T cells in chronic autoantigenic stimulation in MGUS, multiple myeloma and Waldenström’s macroglobulinaemia.
Int J Cancer. 11 February 2015. doi: 10.1002/ijc.29478. [Epub ahead of print] 

Kubuschok B., Pfreundschuh M., Breit R., Hartmann F., Sester M., Gärtner B., König J., Murawski N., Held G., Zwick C., Neumann F.
Mutated Ras-transfected, EBV-transformed lymphoblastoid cell lines as a model tumour vaccine for boosting T-cell responses against pancreatic cancer: a pilot trial.
Hum Gene Ther. 23:1224-36, 2012.

Kubuschok B., Neumann F., Breit R., Sester M., Schormann C., Wagner C., Sester U., Hartmann F., Wagner M., Remberger K., Pfreundschuh M.
Naturally occurring T-cell response against mutated p21 Ras oncoprotein in pancreatic cancer.
Clinical Cancer Research, 12:1365-72, 2006. 

Kubuschok B., Xie X., Jesnowski R., Preuß K.-D., Neumann F., Romeike B., Pistorius G., Schilling M., Scheunemann P., Izbicki J.R., Löhr M., Pfreundschuh M.
Expression of cancer-testis antigens in pancreatic adenocarcinoma cell lines, pancreatic adenocarcinoma and chronic pancreatitis.
International Journal of Cancer, 109: 568-575, 2004. 

Samnick S, Romeike BF, Kubuschok B., Hellwig D, Amon M, Feiden W, Menger MD, Kirsch CM.
p-[123I]iodo-L-phenylalanine for the detection of pancreatic cancer: basic investigations of uptake characteristics in primary human pancreatic tumour cells and evaluation in in vivo models of human pancreatic adenocarcinoma.
Eur J Nucl Med Mol Imaging. 31:532-41, 2004.

Sester M., Sester U., Gärtner B., Kubuschok B., Girndt M., Meyerhans A., Köhler H.
Sustained high frequencies of specific CD4 T cells restricted to a single persistent virus.
Journal of Virology, 76: 3748-55, 2002.

Kubuschok B., Passlick B., Izbicki J.R., Thetter O., Pantel K.
Disseminated tumour cells in lymph nodes as a determinant for survival in surgically resected non-small-cell lung cancer.
Journal of Clinical Oncology, 17: 19-24, 1999.

Complete list of publications by Prof. Dr Boris Kubuschok