The purpose of this study is to compare Lyman-Kutcher-Burman (LKB) model versus Niemierko model for normal tissue complication probability (NTCP) calculation and Niemierko model versus Poisson-based model for tumor control probability (TCP) calculation in the ranking of different treatment plans for a patient undergoing radiotherapy. The standard normal tissue tolerance data were used to test the NTCP models. LKB model can reproduce the same complication probability data of normal tissue response on radiation, whereas Niemierko model cannot reproduce the same complication probability. Both Poisson-based and Niemierko models equally reproduce the same standard TCP data in testing of TCP. In case of clinical data generated from treatment planning system, NTCP calculated using LKB model was found to be different from that calculated using Niemierko model. When the fractionation effect was considered in LKB model, the calculated values of NTCPs were different but comparable with those of Niemierko model. In case of TCP calculation using these models, Poisson-based model calculated marginally higher control probability as compared to Niemierko model.

Regorafenib, an oral small-molecule multi kinase inhibitor, is able to block Vascular Endothelial Growth Factor Receptors (VEGFR-1, 2, and 3), Platelet-Derived Growth Factor Receptors (PDGF), Fibroblast Growth Factor (FGF) receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. Different studies have displayed its antitumor activity in several cancer models (both in vitro and in vivo), particularly in colorectal and gastrointestinal stromal cancers. The mechanism of resistance to regorafenib is largely unknown. In our investigation, we have generated regorafenib-resistant SW480 cells (Reg-R-SW480 cells) by culturing such cells with increasing concentration of regorafenib. Examination of intracellular signaling found that Akt signaling was activated in Reg-R-SW480 cells but not in wild-type SW480 cells, after regorafenib treatment as measured by Western Blot. The Notch pathway is a fundamental signaling system in the development and homeostasis of tissues since it regulates different cellular process such as proliferation, differentiation, and apoptosis and it can be a potential driver of resistance to a wide array of targeted therapies. In this study, we found that Notch-1 was significantly up-regulated in resistant tumor cells as well as HES1 and HEY. Additionally, inhibition of Notch-1 in resistant cells partially restored sensitivity to regorafenib treatment in vitro. Collectively, these data suggest a key role of Notch-1 in mediating the resistant effects of regorafenib in colorectal cancer cells, and also provide a rationale to improve the therapeutic efficacy of regorafenib.

Magnetic resonance imaging remains the gold standard for tumour delineation, but computed tomography with clinical information can give comparable results, which need to be studied further. Computed tomography-based contouring can be used comfortably for delineation of organs at risk.

Sphingosine kinases (Sphk1 and 2) regulate the prodution of sphingosine-1-phosphate (S1P), that is key molecule in cancer development. SphK1, which is commonly overexpressed in malignant tumours, significantly contributes to the pathogenesis of various types of cancer as well as to resistance to different Tyrosine Kinase inibitors (TKIs). Even, SphK2 may promote apoptosis and inhibit cell growth but its role has not yet been fully understood in pathologic conditions. Different growth factorsinduced activation of receptor tyrosine kinases (RTKs) results in production of Sphk1 which catalyzes the phosphorylation of sphingosine. Such enzyme, in turn, is involved in many cellular processes by its five receptors. These are able to transactivate RTKs through amplification of a positive-feedback signaling loop. In conclusion, development of pharmacological inhibitors of SphK1 has been limited by the lack of completely understanding of the enzymatic activation mechanisms of SphK1.

No abstract