1 Mathematical Oncology 2 The Molecular Basis of Synergism between Carboplatin and 3 ABT - 737 Therapy Targeting Ovarian Carcinomas 4

5 Resistance to standard chemotherapy (carboplatin þ paclitaxel) is one of the leading causes of therapeutic 6 failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by 7 members of the Bcl family of proteins including the antiapoptotic protein Bcl-xL, whose expression is correlated 8 with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule 9 inhibitors of Bcl-2/Bcl-xL that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. 10 To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is 11 essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a 12 mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model 13 suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of 14 cells with DNA damage on Bcl-xL for survival. Numerical simulations predict the existence of a threshold of Bcl15 xL below which these cells are unable to recover. Furthermore, coplus posttreatment of ABT-737 with 16 carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical 17 challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug 18 load. We show that the model can be used compute minimal doses required for any desired fraction of cell kill. 19 These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid 20 in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need 21 for close collaboration between modelers and experimental scientists. Cancer Res; 71(3); 1–11. 2011 AACR. 22 Quick Guide to Equations and Assumptions 23 The model schematic for tumor cell growth inhibition 24 mediated by application of carboplatin and ABT-737 is pre25 sented in Figure 1. The following is a brief description of the 26 principal equations and underlying assumptions that drive 27 this reaction diagram. Here, N andM refer to proliferating and 28 arrested tumor cell numbers per well (ovarian cancer cell line 29 IGROV-1), respectively. B, C, X, and P are total unbound Bcl-xL, 30 carboplatin, free ABT-737, and Bcl-xL–ABT-737 complex con31 centration in micromoles per well, respectively. For a detailed 32 description of the model and various terms, we refer the 33 reader to the Supplementary Material.