Cheng Zhou, Md PhD

Therapy induced lung fibrosis constitutes a pivotal dose-limiting side effect of radio-(chemo)-therapy and targeted anti-cancer agents. For development of novel therapeutic strategies, faithful models, reliable quantitative readouts and a better understanding of the mechanism governing lung fibrosis on molecular, cellular and pathophysiological level is needed. Multi-scale characterizations of radiation-induced lung fibrosis (RILF) are pursued to understand temporal dynamic- to dose-response relationship of fibrosis development. The discovery of promising fibrosis related pathways, cell- and gene-regulatory circuitries for rationale design of next generation anti-fibrotic strategies are also investigated.

Emergence of carbon ion radiotherapy (CIRT) is postulated to efficiently eradicate radioresistant tumors. Despite the high-precision of CIRT, the success of this therapy to cure thoracic malignancies will largely depend on the normal lung tissue tolerance limiting administration of a curative dose. Therefore, precise estimation of CIRT induced pulmonary fibrosis, as a critical late side effect, is urgently needed for a successful clinical translation of this promising therapy. The biological evaluation of (sub-) cellular and tissue response to photons, protons and carbon-ions irradiation is urgently needed. Preclinical in-vivo comparison of normal tissue effects such as RILF as a function of different radiation qualities are missing. Herein, the second arm of our work is to develop radiobiological mathematical models for normal tissue response after particle therapy relying on biological surrogates in vivo. The precision determination of the relative biological effectiveness (RBE) of different forms of particle beams such as proton, carbon-ions, helium and oxygen compared with standard clinical megavoltage x-rays has highlighted important issues for therapy using these modalities. Based on our proposed models, a multi-scale estimation algorithm was employed incorporating quantitative imaging, histopathology/immunohistology, clinical chemistry and transcriptomics based disease specific signatures. An improved knowledge of RBEs for a variety of tissues is intended to facilitate clinical particle beam therapy by refining the current treatment models as well as minimizing normal tissue complication probability (NTCP).  

• Multi-scale characterizations of radiation-induced lung fibrosis (RILF)
  • Precision preclinical mouse lung irradiation
  • Development of in vivo surrogates for RILF, i.e., fibrosis index.
  • Characterization of RBE by integrating radiological, transcriptional, proteomic and molecular biological investigations.  

• Molecular mechanisms of RILF
  • Fibrogenesis related immune response
  • The role of senescence in fibrosis development 

• Molecular modulations of RILF
  • Fc-Endostatin
  • CTGF inhibitor (hFG-3019, mFG-3149)
  • DNA-PKcs inhibitor
  • ATM inhibitor 

• Radiobiological modeling of RILF
  • Photons (6MV Linac), Carbon-ions (¹²C)
  • Next trials on Helium (⁴He), Oxygen (¹⁶O) and Protons (¹H)
  • Radiation effects of hypofractionated stereotactic body radiation therapy (SBRT) 

• Personalized normal tissue toxicity
  • Radiation lung toxicity
  • Radiation GI system toxicity
  • Future trials: radiation renal toxicity