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John Poirier
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MS 26 - Re-Modeling Microenvironment Mimicking Human Cancer (ID 548)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Biology/Pathology
- Presentations: 1
- Moderators:P. Yang, C. Mascaux
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 502
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MS 26.04 - PDx Model (ID 7767)
15:30 - 15:50 | Presenting Author(s): John Poirier
- Abstract
- Presentation
Abstract:
The tumor microenvironment differs significantly from the controlled environment of in vitro cell culture. Whereas cell lines are typically grown in plastic vessels containing a pH buffered, nutrient rich liquid medium with 10% fetal bovine serum and incubated at 37 ºC and 5% CO~2~, cancer cells in tumors experience different oxygen tension, growth substrate, nutrient, waste, and growth factor gradients, pH, and the presence of stromal support cells and infiltrating immune cells. The process of establishing a new cell line requires adaptation to this environment, which results in loss of genetic heterogeneity as well as irreversible epigenetic reprogramming that is maintained even when cultured cancer cells are re-introduced to an in vivo setting. Patient-derived xenografts (PDX) are direct human tumor xenografts established and maintained exclusively in mouse hosts. While these models can never perfectly recapitulate an autochthonous human tumor, they are increasingly used as tools in cancer research due to their utility in modeling therapeutic response with higher fidelity than either cell lines or cell line xenografts. A growing interest in defining the role of the tumor microenvironment and in testing the efficacy of immunotherapy in vivo has driven advances in PDX model development. The tumor microenvironment consists of stromal cell components including blood vessels, fibroblasts, and infiltrating immune cells as well as extracellular matrix, growth factors, and nutrients. In PDX, components of the tumor microenvironment are either provided by the mouse host or are excreted by the tumor cells themselves. However, paracrine effects between tumor and stroma may not be entirely replicated in a mouse host due to a lack of cross-species cytokine reactivity. The absence of compatible stroma may bias PDX engraftment toward tumors that are less dependent on paracrine factors or which are more adept at recruiting mouse stromal support cells through enhanced expression of mouse reactive factors. It remains a significant challenge to accurately assess the mechanistic activity of therapeutic approaches designed to inhibit these interactions in the absence of human tumor stroma. Anatomical context can also have significant impact on PDX tumor biology. PDX can be established as subcutaneous flank tumors or at any of a variety of orthotopic sites. Lung PDX are amenable to orthotopic growth in the lung, and can thus be used to model lung cancer growth and metastasis within its normal anatomical context. Orthotopic tumors can have vastly altered metastatic potential and organ preference as well as differential response to anti-cancer therapeutics in comparison to subcutaneous flank tumors. One of the primary limitations of PDX as a model for cancer is the need to use immunocompromised mouse hosts. The degree to which the immune system can be modeled with PDX is dependent on the mouse host chosen and the type of human immune cells used to reconstitute the human immune cell component. PDX can be established in a great variety of different strains of immunocompromised mice including athymic nude mice, severe combined immune deficiency (SCID) and non-obese-diabetic (NOD)-SCID strains, Rag null strains, and profoundly immunocompromised strains in which IL2-Rγc has been disrupted (NSG, NOG, BRG). Each of these strains differs with respect to the type and function of hematopoietic cells. For example, athymic nude mice have intact natural killer (NK) cells, whereas NSG mice do not; NSG mice therefore develop primary tumors and metastases at a much faster rate. Humanized mice are immunocompromised mice that have partially reconstituted human immune components for the purposes of modeling the behavior of the human immune system in a cancer context. NSG, NOG, and BRG mice have been engrafted with isolated peripheral blood mononuclear cells (PBMC) or tumor infiltrating lymphocytes (TIL) primarily to study mechanisms of lymphocyte recruitment; however, a major limitation of this approach is the rapid onset of graft versus host disease in the mouse host. Alternatively, different strains of mice can be engrafted with human CD34+ hematopoietic stem cells (HSC), which results in mouse hosts with fully human lymphocytes, monocytes, dendritic cells and in some cases NK cells. A variety of mouse strains engineered to express human cytokines such as IL-3 and GM-CSF have been developed to promote improved functional human immune system components. PDX models of lung cancer are growing in complexity, variety, and sophistication. These in vivo cancer models will be an integral component in a suite of tools for studying many aspects of lung cancer biology in a research environment. Recent advances in the humanization of mouse hosts promises texpand the possibilities of studying cancer immunology and immunotherapy of human tumors in an experimental setting in vivo.
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OA 08 - Neuroendocrine Carcinoma: Translational (ID 667)
- Event: WCLC 2017
- Type: Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:David S Ettinger, S. Zöchbauer-Müller
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 311 + 312
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OA 08.06 - Exploratory Analysis for Predictors of Benefit of PARP Inhibitor Therapy in Extensive Stage Small Cell Lung Cancer: ECOG-ACRIN 2511 Study (ID 10321)
11:55 - 12:05 | Author(s): John Poirier
- Abstract
- Presentation
Background:
Veliparib, a potent inhibitor of Poly (ADP) ribose polymerase (PARP) enzyme potentiates standard chemotherapy against small cell lung cancer (SCLC) in preclinical studies. The combination of veliparib (V) with cisplatin/etoposide (CE) doublet as first-line therapy of extensive stage SCLC (ES-SCLC) showed significant signal of efficacy with adjusted PFS HR: 0.63 1-sided p=0.01. There was strata by treatment interaction indicating different efficacy benefit in patient subsets (adjusted treatment HR comparing CE+V: CE: 0.34; 80% CI: 0.22 - 0.51; 1-sided p<0.001 for male patients with high tumor burden versus adjusted HR: 0.81 80% CI: 0.60 - 1.09; 1-sided p=0.18 for other patients subsets). We explored clinical and tissue-based biomarkers as predictors of benefit from this treatment strategy.
Method:
Post-hoc analysis of clinical data was conducted to identify clinical differences in patients who derived significant benefit from the experimental therapy. Clinical differences were compared between patients in the control and experimental arms within the patient stratum with significant clinical benefit. Similarly, comparison was performed between the strata. Archival tissue samples collected from patients with ES-SCLC enrolled and treated on E2511 study was employed for biomarker analysis using immunohistochemistry to assessSLFN11 and DNA-PK expression. The study has 88% power to detect a PFS hazard ratio of 0.5 comparing biomarker positive to negative patients using a one-sided 0.025 level logrank test.
Result:
There was an imbalance between control and experimental arms in the Male/abnormal LDH stratum (in strata) with respect to Age: p=0.006; malignant pleural effusion: p=0.095 and T stage: p=0.02. Median PFS was 5.1 mos on CE (95% CI 4.1-6.1) vs. 6.2 mos on CE+V (95% CI 5.9-8.8); HR=0.32, p=0.002 (unadjusted); median OS on CE was 8.8 mos (95% CI 6.6-11.1) vs. 9.5 mos on CE+V (95% CI 7.8-12.8); HR=0.76, p=0.39. Mutivariable analysis controlling for these imbalances still showed a benefit of veliparib (HR=0.26, p=0.001). Comparison of “in strata” group (N=46) to the “not in strata” group (N=82) showed significant imbalance in pleural effusion (p=0.058); elevated AST (p=0.0099) and bilirubin (p=0.0447). Median PFS was identical at 5.9 mos for both groups while median OS was 10.7 mos (95% CI 8.9-13.2) for “not in strata” subsests vs. 8.8 mos (95% CI 7.8-10.8) for “in strata” with a HR of 1.57 (p=0.027) comparing “in strata” to “not in strata”. Outcome differences based on SLFN11 and DNA-PK expression will be presented at the meeting.
Conclusion:
PFS benefit of PARP inhibitor therapy in extensive stage SCLC patients with elevated LDH and male gender was not associated with any other clinical characteristics.
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-001 - SLFN11 Expression in Early Stage Non-Small Cell Lung Cancer Predicts Benefit from Adjuvant Chemotherapy with Taxane and Platinum (ID 9987)
09:30 - 09:30 | Author(s): John Poirier
- Abstract
Background:
No predictive biomarker for cytotoxic chemotherapy is approved for clinical use. Schlafen family member 11 (SLFN11) protein is widely reported as sensitizing to DNA-damaging agents. Epigenetically mediated suppression of SLFN11 is associated with poor response to platinum in patients with ovarian and lung cancer. Pre-clinical lung cancer models suggest that SLFN11 expression may be a useful biomarker of response to cisplatin, PARP inhibitors and topoisomerase inhibitors. Tumor expression of SLFN11 is assessed by immunohistochemistry, RNA expression or DNA methylation; no standard method exists. We used mass spectrometry to quantify SLFN11 protein in archived samples of patients with early stage NSCLC treated with taxane plus platinum (TP) and correlated proteomic expression of SLFN11 with survival.
Method:
We obtained archived tissue sections representing 594 patients with lung cancers of multiple subtypes. A board-certified pathologist marked the tumor areas, which were microdissected and solubilized. In each liquefied tumor sample, 60 protein biomarkers including SLFN11 were quantified with selected reaction monitoring mass spectrometry. Patients were stratified by a SLFN11 cutoff of 100 amol/ug, based on the proteomic assay’s limit of quantification. Survival outcomes were assessed with Kaplan-Meier and Mantel-Cox log-rank analyses.
Result:
Among 86 TP-treated early stage NSCLC patients, those with SLFN11 protein levels above the cutoff (n=51) had better progression-free survival (PFS) than patients with SLFN11 levels below the cutoff (HR: 2.26; 95%CI: 1.08-4.72; p=0.052). Similar differences in PFS were found in the subset of patients with NSCLC (n=77) (HR: 2.79; 95%CI: 1.29-6.05; p=0.030). Differences in overall survival by SLFN11 expression were not statistically significant. In a group of untreated patients (n=440), there were no differences in PFS between patients with high and low expression of SLFN11.
Conclusion:
Mass spectrometric evaluation of SLFN11 retrospectively identified responders to platinum-containing chemotherapy and could be used to predict response for platinum-containing therapy and warrants further validation. Multiplexed proteomics can quantitate SLFN11 simultaneously with other therapeutically relevant proteins (eg, HER2, ALK, ROS1) to inform therapy selection at initial diagnosis and upon relapse.
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P3.15 - SCLC/Neuroendocrine Tumors (ID 731)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.15-008 - [F18]PARPi PET as an In Vivo Pharmacodynamic Biomarker of PARP Inhibitor Therapy in Patient-Derived Xenografts of Small Cell Lung Cancer (ID 10378)
09:30 - 09:30 | Author(s): John Poirier
- Abstract
Background:
Inadequate drug delivered to target tumors contributes to ineffective treatment. However, the delivered drug concentration is difficult to assess in patients in a timely and clinically-relevant manner. To address this barrier to PARP inhibitor(PARPi) therapy, we evaluated a radiolabeled PARP inhibitor([F18]PARPi) as a pharmacodynamic biomarker. We hypothesized that [F18]PARPi PET imaging can measure PARP inhibitor concentration and activity intratumorally, thereby, predicting therapeutic efficacy. Here, we applied this approach to patient-derived xenografts(PDX) of small cell lung cancer(SCLC).
Method:
To study [F18]PARPi PET as a biomarker of talazoparib(TAL), SCRX-Lu149 PDXs were orally gavaged with different doses of TAL. Mice were injected with [F18]PARPi and imaged with PET, with the expectation that TAL would competitively block [F18]PARPi binding to PARP. Organ retrieval and gamma counting was performed for drug and radiotracer biodistribution. Ex vivo PARP enzymatic activity was measured by ELISA of PAR levels. Differences in PET uptake and the tumor volumetric endpoint (time to reach 1000 mm[3]) were analyzed by student t-test and the log-rank test, respectively.
Result:
In PK PET imaging with 0.2 mg/kg TAL, greatest blocking of the radiotracer was noted at 1 hour after gavage with less blocking as time from dosing was extended (avg of 3 mice: 4.5, 2.2, 2.7, 3.1, and 3.4% max injected dose per gram [ID/g] for untreated, 1, 3, 6, and 24 h after drug, respectively). [F18]PARPi PET differentiated between doses of 0.1 and 0.3 mg/kg TAL at 3 h after dosing (3.9 vs 2.1% ID/g or 13% vs 53% relative blocking, respectively; p=0.003). No differences were noted in heart, lung, esophagus, muscle, or bone. PET uptake correlated with ex vivo enzymatic inhibition/PAR levels (p=0.0009). PET measured differences in drug doses corresponded with improved outcomes for PDXs treated with 0.3 mg/kg in combination with radiotherapy(RT; median 84 days, p=0.04) but not 0.1 mg/kg + IR (66 days) compared to RT alone (52 days).
Conclusion:
[F18]PARPi PET can differentiate between multiple doses and timing of orally administered TAL and correlates with drug efficacy. This likely reflects differences in intratumoral drug level and demonstrates the potential of this PET radiotracer to assess differences in drug delivery and efficacy for patients treated with PARP inhibitors.
