Program 4: Innovative therapy

Program leaders

Prof. R. de Bree, MD, PhD (Otolaryngology/Head and Neck Surgery)
J.J.W.M. Janssen, MD, PhD (Hematology)
Prof. G.J. Peters, PhD (Medical Oncology)
Prof. S. Senan, MB, BS, PhD (Radiotherapy)
H. van der Vliet, MD, PhD (Medical Oncology)

Description

The VUMC CCA program 4 encompasses translational research within the field of oncological and immune-mediated, non-malignant diseases and focuses on the following two research lines:

Targeted therapy, including radiotherapy, surgery and systemic therapy
Immunotherapy

The major aim of the program is to explore potential synergies when innovative and targeted therapies are combined with classical treatment modalities like radiotherapy, surgery and chemotherapy for malignant diseases and to discover new treatment modalities for immunological diseases. This includes pre-clinical evaluation and clinical application of the new generation of the so-called molecular targeted therapies against novel cellular targets, anti-angiogenesis agents and the pharmacological optimalization of conventional cytotoxic and antirheumatic drugs. Identifying novel targets and in-house drug discovery for which (pharmaco)genomics and proteomics are essential techniques, as well as investigating mechanisms of drug resistance are a key focus. Program 4 is therefore strongly intertwined with VUMC CCA program 3. Preclinical and early studies in radiotherapy currently focus on combining radiotherapy with radiosensitizing molecular targeted therapies, with the aim of developing experimental arms for future clinical trials. Another active area of research is the optimisation of 4-dimensional image-guided approaches that aim to improve local control and reduce normal tissue toxicity.

The program encompasses the work of many Clinical Departments involved in clinical cancer research. It remains a fact that a significant number of them do not actively focus on clinical translational research, but are instead major referral centers for distinct immunological and malignant diseases. In case of the latter, the clinical activities of such departments have led to recognition as national referral centers for some disease types, have stimulated patient accrual to novel clinical trials, gained access to new drugs, have facilitated useful contacts with pharmaceutical companies, and have resulted in key clinical publications. It is expected that the contributions of such clinically-oriented departments will continue to add to high-quality output of program 4

As lack of immunological control probably plays a major role in the pathogenesis of auto-immune diseases and malignancy, it is self-evident that the research line Immunotherapy focuses on new immunotherapeutic approaches for both the treatment of rheumatoid arthritis and other immunological disorders as well as for malignant diseases. For example, a major focus of immuno-therapy of malignant disorders is evaluating the role of vaccination in the adjuvant and primary settings. Improved survival rates are now achievable for a number of common malignancies by using combined modalities. Collaboration with program 2 has been initiated and will be broadened in next years.

Perspectives

In the next five years, specific patient-tailored therapies will be developed in a range of malignant diseases. These therapies will be directed at defined cellular, tumor-specific- and tumor environment targets, like phosphoproteins and tumor cell membrane antigens. In tumors where malignant stem cells can be identified, we will aim at stem cell specific targets. To prevent toxicity and increase anti-tumor activity of existing and newly developed agents, a major effort will be put on characterization of genetic polymorphisms affecting pharmacokinetics and -dynamics and that predispose to development of adverse reactions. Where applicable, the new techniques will be used, in concert with image-guided controlled radiotherapy and surgery to further refine the concept of personalized tailored therapy. The existing expertise of both the VUMC micro-array facility and the VUMC OncoProteomics Laboratory will form a solid extension to facilitate these aims. Furthermore, effective dendritic vaccines will be developed and evaluated in clinical studies of various malignancies. By exploiting the existing expertise within the VUMC CCA in immune effector-targeted approaches in cancer therapies, novel immune-therapies will also be explored in treating auto-immune disorders.

Research aims for the coming 5 years

Increase translational research with a focus on the early clinical application of relevant discoveries. The process of clinical evaluation may range from early studies of feasibility and toxicity based on results of (phospho-)proteomics to the validation of efficacy of new techniques, drugs or vaccines.
Focus on targeted therapy in all its forms, including pharmaceuticals, radiation, immunotherapy and surgery, directed at the deregulated cell (arising from either malignant or immunological dysfunction) so as to improve efficacy and minimise collateral damage to normal tissues. Where possible, specific malignant stem cell directed therapy will be explored.
Design of clinical phase I,II and III trials will be integrated in the existing lines of translational and immunological research.
Existing expertise in both immunology, oncology and imaging will be exploited in order to develop novel therapeutic approaches.

Collaboration

In VUMC

A large number of departments are involved in program 4. Translational researchers in program 4 are now working in close contact with more fundamental/pre-clinical researchers from program 1-3 in order to allow the transition of bench-to-bedside research.
Information about the research meetings of all the departments in program 4 is now disseminated via the VUMC CCA website to stimulate cooperation among the different departments. It is anticipated that this will increase the cross-pollination of oncological and immunological research.