From bench to bedside: lessons learned in translating preclinical studies in cancer drug development

Abstract

The development of targeted agents in oncology has rapidly expanded over the past 2 decades and has led to clinically significant improvements in the treatment of numerous cancers. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. As preclinical studies shift toward defining proof of mechanism, patient selection, and rational drug combinations, it is critical to understand the lessons learned from prior translational studies to gain an understanding of prior drug development successes and failures. By learning from prior drug development, future translational studies will provide more clinically relevant data, and the underlying hope is that the clinical success rate will improve and the treatment of patients with ineffective targeted therapy will be limited.

Figure 1.

Preclinical studies investigating epidermal growth factor receptor inhibition in colorectal xenografts correlated with improved patient outcomes. A) Growth inhibition of a preclinical study of CPT-11 refractory colorectal tumor xenografts in nude mice. Mice with established DLD-1 (a) or HT-29 (b) tumors were treated with two cycles of CPT-11 therapy (100mg/kg) on days 0 and 7. Mice with tumors that did not respond to CPT-11 therapy (defined as >2× initial tumor volume at day 12; shown as dotted vertical line) were selected, randomized, and then treated with IMC-C225 at 1mg/dose/every 3 days (•), continued CPT-11 at 100mg/kg/week (□), or received combination therapy (▪). Bars represent standard error (14). B) Time to disease progression in two study groups on a phase III clinical trial investigating cetuximab as monotherapy or in combination with irinotecan, in patients refractory to irinotecan (18). Reprinted with permission from the American Association for Cancer Research and the New England Journal of Medicine.

Figure 2.

Preclinical studies in patient-derived human tumor xenograft (PDTX) models correctly predict lack of response to epidermal growth factor receptor (EGFR) antibodies in KRAS-mutant colorectal cancer (CRC). Results from a retrospective analysis evaluating the effect of KRAS mutational status on overall survival in patients treated with cetuximab (A, B) and results from a PDTX trial evaluating the effect of KRAS mutational status on overall survival in PDTX patients treated with cetuximab (C, D) (24). KRAS-mutant PDTX patients treated with cetuximab had similar survival curves compared with control (CTRL) PDTX patients (C). KRAS wild-type PDTX patients treated with cetuximab had statistically significantly improved survival compared with control PDTX patients (D). The results from the xenopatient trial mirror the results seen clinically, suggesting that the lack of efficacy of EGFR monoclonal antibodies in KRAS-mutant CRC could have been predicted preclinically (34). Reprinted with permission from the New England Journal of Medicine and the American Association for Cancer Research.

Figure 3.

An example of bedside-to-bench-and-back approach with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in non–small cell lung cancer (NSCLC). Bedside to Bench: Retrospective analysis of multiple phase III studies of an EGFR TKI in NSCLC revealed that responders to the EGFR TKI were enriched with activating EGFR mutations (MT) (eg, L858R, deletion in exon 19), whereas nonresponders were enriched for EGFR wild-type (WT). The protein structure of EGFR with activating mutation L858R illustrates the binding of gefitinib in the ATP-pocket (protein databank code: 2ITZ). More than 60% of the responders eventually acquired secondary mutations and progressed on EGFR TKI therapy. One of the most common secondary acquired mutations was the “gate-keeper” mutation of EGFR T790M. Protein structures of the wild-type T790 (PDB code: 2ITY) and acquired mutation T790M (PDB code: 3UG2) are shown. Multiple preclinical studies have been conducted to understand and overcome this resistance mechanism. One of these studies conducted by William Pao and colleagues (32) employed a genetically engineered mouse model that harbors this mutation. They observed that tumors regressed in the combination arm of a second generation EGFR TKI (BIBW2992) that inhibits both EGFR and HER2 with the monoclonal antibody EGFR cetuximab; the activity of this combination was statistically superior compared with the individual treatment arms (BIBW2992 or cetuximab). Bench to Bedside: A phase I clinical trial is currently open to investigate the combination of BIBW2992 and cetuximab in NSCLC patients that progressed after EGFR TKI (ClinicalTrials.gov ID: NCT01090011).

Figure 4.

Preclinical microvessel density studies have not accurately predicted clinical efficacy with angiogenesis inhibitors. A) A preclinical study of vatalanib (PTK787) in H1975 non–small cell lungt cancer (NSCLC) xenografts exhibits statistically significant changes in tumor microvessel density index (MDI), tumor vessel size (VSI), and apparent diffusion coefficient (ADC). The blue bars represent vehicle-treated tumors, and the red bars represent vatalanib-treated tumors (224). B) Kaplan–Meier plots for progression-free survival (PFS) in patients with NSCLC treated with vatalanib in a phase II clinical trial demonstrating a median PFS of 2.1 months (225). Reprinted with permission from PLoS One and Oxford University Press.

Figure 5.

Results of a bench-to-bedside study of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) after treatment of mice and patients with G6-31. A) Ex vivo evidence for rapid antivascular effects of G6-31. Representative micro–computed tomography angiographic data for each treatment group is shown at 90 minutes, 24 hours, and 48 hours. The extracted vascular network (red) and the entire tumor (gray) are shown. B) Representative MRI parameter maps from one patient. a) Map of enhancing voxels demonstrates a statistically significant decrease in blood flow beginning at 48 hours that persists through day 12. b) Map of fractional blood plasma volume (v _p) also demonstrates a statistically significant decrease, beginning at 4 hours that persists through day 12. c) Map of the K ^trans exhibit reduction in blood flow within 4 hours that persist at 48 hours and day 8, but returns to baseline levels by day 12. These changes are consistent with reduction in either vessel permeability and/or blood flow (147). Reprinted with permission from the American Association for Cancer Research.

Figure 6.

Preclinical studies of bortezomib in multiple myeloma cell lines accurately predicted benefit in patients with multiple myeloma. A) Preclinical study of bortezomib vs dexamethasone against multiple myeloma cell lines. Dexamethasone in control media (□) and with bortezomib 0.0025 (□) or 0.005 (■) × 10⁻⁶ M. The preclinical study demonstrates statistically significant activity of bortezomib compared with dexamethasone (172). B) Progression-free survival in a phase III clinical trial of bortezomib vs dexamethasone in patients with multiple myeloma. A statistically significant increase in progression-free survival was seen in patients receiving bortezomib compared with patients receiving dexamethasone (177). Reprinted with permission from the American Association for Cancer Research and the New England Journal of Medicine.

Figure 7.

A potential future bilateral biomarker development strategy. The future of drug development likely will take on a bilateral approach, in which drug responsiveness signatures are developed in cell lines and patient-derived xenograft models in concert with the comprehensive molecular categorization of patient tissues. Thus, drug responsive signatures can then be directly indexed against clinical samples, facilitating patient selection. COSMIC = Catalog of Somatic Mutations in Cancer; ICGC = International Cancer Genome Consortium; MUT = mutant; TCGA = The Cancer Genome Atlas; RES = resistant; SEN = sensitive; WT = wild-type;