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e15078 Background: Esophageal squamous cell carcinoma (ESCC) is a deadly malignance prevalent in parts of China and no target therapy option. Cetuximab, approved for treating subset of metastatic c...

e18505 Background: Patient-derived xenograft (PDX) is increasingly used to evaluate oncology drugs. PDX, reflective of original patient pathology and genomics, is predictive of response to treatmen...

e15009 Background: For many cancers, chemotherapy is a major or even the only treatment option, but unfortunately without ultimate proof of clinical benefits in many cases, e.g. improved PFS/OS. In...

3544 Background: Cetuximab was approved for treating EGFR-expressing metastatic colorectal carcinoma (mCRC) without patient stratification. Subsequent retrospective clinical studies resulted in an exclusion criterion for patients with KRAS mutations at codons 12 and 13. However, only a fraction of patients with wtKRAS benefit from the treatment. Recent analyses indicated that patients with KRAS mutation at codon 13 can also benefit. We set out to investigate whether KRAS mutations, or any other factors, are good biomarkers for CRC-cetuximab therapy patient stratification. Methods: We have established patient derived xenografts (PDX) from treatment-naive Asian CRC patients to discover biomarker predictive of cetuximab response. We conducted a clinical trial style study (“patient avatar trial”) of cetuximab using a randomly selected cohort of 26 EGFR+ PDXs. The antitumor activities were analyzed against KRAS mutation status and a published expression-signature. Results: We identified 12/26 (~46%) as cetuximab responders and 14/26 non-responders (defined by 50% tumor growth inhibition threshold). All 14 non-responders are mutated for one or more of KRAS, BRAF (V600E), EGFR, AKT and PIK3CA oncogenes. In contrast, 5/11 responders analyzed are wild-type for all these genes. Importantly, 5/11 responders have activating KRAS mutations at codons 12/13, contradictory to the currently practiced clinical exclusion criteria, but consistent with more recent clinical findings. Most interestingly, the observed cetuximab activity in this cohort of 26 PDXs has a surprisingly strong correlation to a published RAS pathway score. Conclusions: Our results indicated strong predictive power of cetuximab-CRC-PDX trial and RAS signature, and warrant prospective clinical studies for further confirmation.

e14612 Background: Most anticancer drug candidates, currently in clinical trials, have clear targets in molecular and cellular systems. However, such molecular targets are not always affected (or not correlated with efficacious endpoints) when the candidate is evaluated in a clinical setting. There is an urgent need to develop better biological tools and models to ease the transition between in vitro and in vivo, and between preclinical and clinical settings. Activation of tyrosine kinases in tumor cells has been recognized as key driving force in malignancy; therefore inhibitors of tyrosine kinases (TKI) have often shown efficacy in preclinical in vivo models and beneficial responses in clinical trials. An increasing number of TKI has been approved as anticancer drugs in selected cancer types. Methods: We have developed a unique platform combining our novel HuPrime™ xenograft models with our PD biomarker technologies. This platform is used to better understand the efficacy of novel drug candidates and generate information critical to maximize the chance of a successful clinical development. To illustrate the usefulness of our platform, we have applied it to understand the pharmacodynamic changes (at the molecular level) which are associated with the activity of sunitinib and sorafenib in our sensitive esophageal HuPrime models. Tumor tissues from sensitive esophageal HuPrime models treated with single dose of the respective drugs (and a vehicle control) have been collected at time-points 4, 8, 16, and 24 hour. Results: We have successfully applied immunohistochemistry (IHC) assays on many molecules covering most pathways including proliferation, apoptotic, necrotic, and cell cycle regulation, G2M phase arrest, DNA damage response, etc. Additional markers including angiogenesis can also be included for certain therapeutic compounds. These tissues have been analyzed with our platform and we have uncovered key molecular events which correlate with the efficacy and potency of the drugs. Conclusions: The PD biomarkers validated in this approach have potential for clinical application and patient stratification. [Table: see text]

11008 Background: New oncology drug development has moved from general cytotoxic agents to molecular target-directed therapeutics. Consequently, there is a need to identify tumor types and individual patient tumors that express the target and could benefit from more selective therapies in clinical trials. Therefore, the in vivo models used in preclinical development should be“disease-oriented” and target-directed. Recently, we developed non-small cell lung cancer (NSCLC) xenograft models by transplanting human fresh tumor fragments into nude mice, which have been used for test of cytotoxic and targeted anticancer drugs. Methods: The fresh NSCLC tumors were collected from local hospitals. The tumor fragments were subcutaneously implanted into nude mice. The EGFR and K-ras mutation status of the tumors were investigated and compared with the efficacy results. The test drugs included paclitaxel, gemcitabine, and the epidermal growth factor receptor (EGFR) inhibitor erlotinib. Results: A total of 72 NSCLC samples were implanted, and 13 tumor models were established (tumor taking rate 18%) for the first passage. The tumor taking rates were higher in the second and third passages (80–100%). Paclitaxel and gemcitatbine produced tumor growth inhibition rates of 50–53% regardless of the EGFR and K-ras mutation status. While erlotinib demonstrated a significant antitumor activity only in the tumors bearing EGFR mutation with wild-type K-ras, which were consistent with their clinical findings. The tumor xenografts’ architecture, the cell and histopathological morphology from the three generations mirrored the original patient cancers. Conclusions: These results suggest that human primary tumor xenograft models provide a unique renewable source of tumor material for test of novel anticancer agents. They may predict more relevant clinical response rates and higher correlation with clinical findings than use of xenograft models established from long-term cultured cancer cell lines, especially for test of target-oriented therapeutics in new drugs development programs. No significant financial relationships to disclose.