Radiation Oncology

Radiation Biology Research Laboratory (page 2)

III. Current Research Areas in the Department

1. Etiology of Radiation induced chromosomal aberrations.
Nonrandom chromosomal translocations are frequently found in childhood and adult leukemias and also in solid tumors. Oncogenic chromosomal translocations not only contribute to carcinogenesis, but also help doctors properly diagnose patients, select the best treatment protocols, and predict the prognosis of these diseases. Despite the key importance of chromosomal translocations to these diseases, the molecular mechanisms leading to chromosomal translocation are not well understood yet. The most widely accepted model suggests the role of DNA double strand breaks (DSBs) and inappropriate repair of these breaks by non-homologous end joining (NHEJ), one of two main pathways repairing DSBs in eukaryotes for chromosome translocations.



To define molecular basis of chromosomal translocations, the research group headed by Dr. Lee developed a yeast-based model system to induce NHEJ-mediated chromosome translocation between two DNA DSBs formed in vivo. NHEJ-mediated reciprocal chromosome translocation is followed in real time in experimental setting and identified several gene products that suppress joining of broken chromosome ends between different chromosomes. Most importantly, mutations of genes identified by these studies are known to predispose patients to chromosomal translocations and lymphoid malignancy, representing potential biomarkers and drug targets. Using this model system, the ongoing research focuses on addressing two fundamental questions: why are specific chromosomal translocations recurrent in certain cancers? Why do chromosomal translocation breakpoints contain microhomology?


2. Chemotherapeutic Drugs and Radiation
Chemotherapuetic resistance is a major hurdle to improving the survival rates from metastatic solid cancers. XPF/ERCC1 belongs to an evolutionary conserved member of structure specific DNA endonuclease complexes that include Mus81/EME1, and FANCM/FAAP24. All the members of these nuclease family participate in the repair of a wide range of DNA lesions including those induced by environmental toxins and radiation exposure such as UV induced bulky adducts, inter-strand cross-links (ICL), DNA double strand breaks (DSBs), and stalled and collapsed replication forks. Accordingly, XPF/ERCC1 mutations in mouse and humans exhibit severe sensitivity to genotoxic chemicals and sunlight exposure, predisposing patients to skin cancer, leukemia, neuro-degeneration, developmental abnormality and accelerated aging. Most importantly, drug resistant tumors express elevated level of XPF/Ercc1 nucleases, underscoring the importance of this enzyme in the prognosis of anti-cancer therapeutics.

Biochemically, XPF/ERCC1 (and its budding yeast homolog Rad1/Rad10) is a DNA endonuclease with two distinct substrate specificities. In one hand, XPF/ERCC1 produces a nick 5' to the UV-induced lesion. This activity then renders excision of the strand harboring UV lesions or chemically induced bulky adducts and confers resistance to UV exposure and suppresses skin cancers. In addition, XPF/ERCC1 cleaves at a branch point containing 3' DNA flaps (single strand overhangs). This activity is important for homology dependent forms of repair including homologous recombination (HR) and single strand annealing (SSA). Puzzlingly, however, we still do not know which of these two activities are responsible for repairing DNA lesions, especially those induced by anti-cancer therapeutics. Deciphering the precise role(s) of XPF/Ercc1 in repair of genotoxic chemicals and applying such knowledge to therapeutic application will help develop more effective strategies to treat these diseases and improve the prognosis.

Currently, we are investigating the role of XPF/ERCC1 in the repair of DNA lesions induced by platinum based drugs and other widely used chemotherapeutics. We are also screening small molecule inhibitors that selectively disable 3' flap endonuclease activity of the complex but sparing the UV lesion incision activity or vice versa. Such compounds will emerge as an excellent therapeutic and research tool to target biological functions associated with XPF/ERCC1 3' flap nuclease with no adverse effect on the sunlight sensitivity.


3. P53 based strategy to reduce the toxicity of radiation therapy and chemotherapy
One of the major pathways radiation therapy or chemotherapy causes normal tissue toxicity is activation of p53 that leads to cascade of events that eventually leads to cell death. Our team of researchers has demonstrated that very low dose arsenic, by temporarily and reversibly suppressing p53 activation at the time of treatment with radiation or chemotherapy, reduces the normal tissue toxicity of these treatments without compromising tumor response to treatment. This selective protection of normal tissue is possible because this strategy requires normal functioning p53. Essentially all of the cancer cells have either mutated or dysfunctional p53 and therefore are not protected. This particular p53 pathway has been also demonstrated to be independent of tumor suppressor pathway of p53, negating the concern that suppression of p53, even though temporary, could contribute tumor development or progression. The other concern about using very low dose arsenic is possible tumor genesis as arsenic is a known carcinogen. However, it has been also shown that a certain cumulative threshold dose of arsenic is needed for mutagenesis and the dose used for cytoprotection with our strategy is far below this threshold. At molecular level, it has been demonstrated that totally different sets of genes are expressed depending on the dose of arsenic in vitro, supporting out strategy.

We have taken this strategy from in-vitro to in-vio and eventually to a clinical trial. In a pilot phase II clinical trial that was completed in 2013, we found the dose of arsenic that temporarily and reversibly suppresses p53 activation. We also identified chemotherapy regimens whose myelosuppressive effects could be ameliorated by this dose of arsenic. We are in the process of setting up a confirmative phase II trial with one of these regimens at this point.

We have also expanded this strategy to protect the bone marrow from Y-90 ibritumomab tiuxetan. Y-90 ibritumomab tiuxetan is used to treat B-cell lymphoma, especially indolent follicular lymphoma. Though it is a very effective against these lymphomas, its main toxicity has been myelosuppresion and potential contribution to development of myelodysplastic syndrome (MDS). Our in-vivo data have demonstrated that a brief pretreatment with low dose arsenic can not only protect the bone marrow from Y-90 ibritumomab tiuxetan but also stabilize the DNA during the treatment, raising the possibility that it could help reduce the development of MDS. We are currently working on taking this finding to a clinical trial.

Another area we are working on to expand this strategy is development of preclinical models for protection of the brain from radiation therapy. We hope to be able to take this into clinical trial in the near future.



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