New strategies for improving the efficacy of breast cancer therapy using the CETSA technology for drug-target interaction studies along with detailed molecular analyses

CETSA-breast cancer group, PI Jonas Bergh

Contact person  Jonas Bergh

Keywords: CETSA, breast cancer, target engagement, therapy, molecular characterisation

Project description

Our planned studies will be highly informative with potential to better select therapies, by utilizing our breakthrough technology, the Cellular Thermal Shift Assay (CETSA), to establish novel diagnostic strategies for guiding personalized breast cancer therapy. Targeted drugs are compounds that have been developed to interact with specific proteins in target cells. In order to be effective, the compound should be present in sufficient concentration to bind the target and exert its effect. Our technology CETSA for the first time directly measures target engagement – the amount of a drug compound that reaches and binds its target protein – in cells, animals and patient samples.

We aim to confirm drug target engagement and relate it to therapeutic efficacy in breast cancer patients. Initially, CETSA will be further optimized using cell lines and animal models. Thereafter, we aim to relate the CETSA findings to therapeutic efficacy in breast cancer patients to study patient-related outcome, using already operated breast cancers. A small piece from each tumor will be exposed to standard breast cancer drugs, to validate the specificity and sensitivity of CETSA for relevant drug-target pairs; detailed molecular characterization will be performed for correlative studies. Next, we will test CETSA on biopsies from patients with recurrences. Thereafter, we will use breast cancer biopsies from patients planned for neoadjuvant therapy (treatment given before surgery), to test our hypothesis that CETSA based biomarkers can predict drug treatment outcome. Biopsies taken before treatment will be tested by CETSA and molecular characterization. The patient will then be given therapy according to clinical standard. After drug exposure, a second biopsy will be taken to validate the first test. CETSA is a new method and needs further evaluation before implementation in clinical routine; however, the long-term goal is to in an early stage be able to reveal the potential of success versus failure of a specific drug. The final test will be a prospective and randomized study; CETSA and molecular profiling for drug selection and dosage vs. best standard care – drug selection.

Internal network

Prof. Jonas Bergh, Department of Oncology-Pathology, Karolinska Institutet & Radiumhemmet, Karolinska University Hospital, Prof. Pär Nordlund, Department of Oncology-Pathology, Karolinska Institutet, Prof. Yihai Cao, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Prof. David Lane, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Dr. Sara Lööf, Department of Oncology-Pathology, Karolinska Institutet, Assoc. Prof. Johan Hartman, Department of Clinical Pathology, Karolinska University Hospital and Department of Oncology-Pathology, Karolinska Institutet, Dr. Johanna Klinge, Department of Oncology-Pathology, Karolinska Institutet, Dr. Irma Fredriksson and Prof. Jan Frisell at the Department of Surgery at Karolinska University Hospital.

External Links

Dr. Daniel Martinez Molina, Dr. Eva Backström Rydin and Dr. Michael Dabrowski at Pelago Bioscience, Assoc. Prof. Theodoros Foukakis and Assoc. Prof. Thomas Hatschek, Department of Oncology-Pathology, Karolinska Institutet & Radiumhemmet, Karolinska University Hospital.

Resources used

Established biobanks, SciLifeLab, the Clinical Trials Unit at Karolinska University Hospital

Publication list

  1. Lindström L, Karlsson E, Wilking U, Johansson U, Hartman J, Lidbrink E, Hatschek T, Skoog L, Bergh J. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol, 2012;30(21)2601-8. Impact factor: 18.443
  2. Martinez Molina D, Jafari R, Ignatushchenko M, Seki T, Larsson EA, Dan C, Sreekumar L, Cao Y and P Nordlund. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science. 2013; 341(6141):84-7. Impact factor: 33.611
  3. Savitski MM, Reinhard FB, Franken H, Werner T, Savitski MF, Eberhard D, Martinez Molina D, Jafari R, Dovega RB, Klaeger S, Kuster B, Nordlund P, Bantscheff M, Drewes G. Tracking cancer drugs in living cells by thermal profiling of the proteome. Science. 2014;346(6205):1255784. Impact factor: 33.611
  4. Cortazar P, Zhang L, Untch M, Mehta K, Constantino J, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain S.M, Prowell T, Loibl S, Wickerham L, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas E, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara M, Fasching P, Zujewski J-A, Slaets L, Tang S, Gerber B, Geyer C, Pazdur R, Ditsch N, Rastogi R, Eiermann W, and von Minckwitz G. Pathological Complete Response in Breast Cancer: CTNeoBC Pooled-Analysis. Lancet 2014; 384: 164-172. Impact factor: 45.217
  5. Bergh J, Pritchard KI, Cameron D. Sisyphean Efforts: Establishing the Correct Risk-Benefit Balance for Adjuvant Therapies. J Clin Oncol, 34:895-7, 2016 J Impact factor: 18.443