It is critical to recognize that although radiation is rarely curative on its own, it plays a central role in achieving local cancer control for most cancer types. This is an extremely important endpoint for cancer patients, as there are few options for those who fail locally, even where systemic (distant) disease is controlled. Needless to say, as medical management of cancer has improved, and more cancer patients are being cured of their systemic cancer, toxicity is also an extremely important endpoint for cancer patents. Toxicity from radiation is a result from both local, DNA-damage of surrounding tissues, as well as the immune response to radiation. There are very well defined toxicity metrics for cancers treated with radiation, especially lung, prostate and head and neck, reflecting both short term and long-term toxicities. One of the primary focuses in the field of Radiation Oncology is to balance the opportunity to achieve local tumor control with the risk of causing the patient long-term toxicity.
To achieve this goal, our Biobanking Core collects, transforms and studies the genetics of our patients, and is linked to all of the clinical data being prospectively collected in our department. This has enabled us to begin developing meaningful genetic diagnostics to better direct radiation treatment.
Our Biobanking Core also isolates immune cells to better understand the role of the immune system across patients and its association with local control, systemic control and toxicity. We perform analyses of serum and cells to assess immune function before, during and after therapy. Tumor-specific responses and immune profiling is primarily based on 14-color flow cytometry for immune cell subsets and tetramer analyses. Experience with Elispot and intracellular cytokine assays is also available. Serum/plasma samples are generally used for cytokine and other analyses. We were the first to show clinically that radiotherapy acts as an in situ vaccine, generating tumor-specific immune responses during and after therapy. At the same time, immune function is imbalanced by the cancer and some patients with autoimmune diseases, such as scleroderma, are known to be radiosensitive through altered immune function. Thus, baseline differences in immune function can both help, and hurt a patient receiving treatment.
These clinical observations interface with a strong pre-clinical immunology program that has shown that the power of radiation to act as an immune adjuvant is dependent on the size of the dose per fraction and that myeloid and lymphoid regulatory cells are generated following tumor irradiation in addition to positive tumor-specific immunity. Blocking their involvement increases the extent of local tumor regression and decrease micrometastatic disease. Clinically, this will be achieved in the near future using immune checkpoint inhibitors. Currently, blocking TGF-b is one approach being tested in the clinic in patients with advanced breast cancer in collaboration with NYU, with immune monitoring being performed by our Immune Monitoring Core. The Immunology and Radiotherapy projects in DMCO have longstanding collaborations with the Tumor Immunology Program at UCLA.
The normal and cancer stem cell radiobiology research program is 40 years old and the oldest experimental research program of the Department. Founded by Dr. Rodney Withers, it has defined the biological key principles of modern radiotherapy. The program continues in-depth exploration and understanding of the heterogeneity of normal tissues and cancers and their response to radiation. Results from this program have been and continue to be fundamental for radiation protection and mitigation research, biomarker discovery and the DMCO immunology program. The current normal stem cell program is focused on novel mitigation strategies for hematopoietic stem cells, intestinal stem cells and neural stem cells.
With the advent of markers during the last 10 years to identify cancer stem cells prospectively, the field in general has gained tremendous new momentum and the DMCO has been at the forefront of this research field. The DMCO has recently made seminal contributions to the fields including the first description of radioresistance of breast cancer stem cells, the development of the first in vivo imaging and tracking system for cancer stem cells, the first description of the metabolic state of cancer stem cells, and the discovery of radiation-induced reprogramming of non-tumorigenic cancer cells into cells with an induced cancer stem cell phenotype.
The cancer stem cell research program targets a variety of tumor entities including breast cancer, head and neck squamous cell carcinoma, glioblastoma, and prostate cancer. Current funded and developmental highly translational research projects include targeting cancer stem cell metabolism, refinement of our cancer stem cell imaging system, and the discovery of novel targeted therapies against cancer stem cells and their induction through ionizing radiation. The translational program is complemented by a basic science research program uncovering the molecular mechanisms of various aspects of cancer stem cell and proteasome biology.
Many lines of evidence point to damage of tumor DNA damage as a primary therapeutic mechanism of radiotherapy. Therefore, modulation of the DNA-damage response or interference with DNA repair after radiotherapy could be a useful therapeutic strategy. The DMCO is involved in the development and assessment of small molecules that interfere with DNA repair and DNA damage sensing for use as cancer therapeutics.
The DMCO has strong interest in signal transduction pathways, in particular their relationship with response to radiation therapy. Silencing of suppressors of cytokine signaling (SOCS) proteins occur in many cancer types and affects their intrinsic radioresistance. These studies also provide a platform for investigation of several commercially available drugs that might synergize with radiotherapy in this and other diseases. We work closely with Trio investigators to extend the tumor profiling that they have performed to include radiation response. For example, we have provided data on radiosensitization by poly ADP ribose polymerase inhibitors (PARPi) in vitro and in vivo that we hope will allow them to enter clinical radiation therapy trials in head and neck and prostate cancer at UCLA.