Abstract
Fifty percent of patients with localized triple negative breast cancer (TNBC) have substantial residual cancer burden following treatment with neoadjuvant chemotherapy (NACT), resulting in a ...40-80% risk of recurrence which leads to distant metastases and death for most patients. Intra-tumor heterogeneity (ITH) is a pervasive feature of TNBCs but the relative contributions of heterogeneous tumor cell populations to chemoresistance are not understood. To investigate the clonal dynamics that accompany chemotherapy treatment, we employed orthotopic patient-derived xenograft (PDX) models of treatment-naïve TNBC, thus enabling experimentation with heterogeneous populations of human tumor cells that have undergone minimal manipulation.
To monitor the fates of PDX tumor cell lineages undergoing treatment with front-line NACT, we treated multiple treatment-naïve PDX models with Adriamycin combined with Cytoxan (AC). Some PDXs initially exhibited partial sensitivity followed by maintenance of residual tumors that were resistant to chemotherapy. Residual tumors re-grew to regain partial chemo-sensitivity. To conduct barcode-mediated clonal tracking, we introduced a pooled lentiviral barcode library (Cellecta; 50M unique barcodes) into freshly dissociated PDX tumor cells which were orthotopically engrafted into recipient mice. Strikingly, residual tumors maintained the same clonal architecture as untreated tumors. In contrast, only 20% of residual tumor clones repopulated tumors after discontinuation of treatment. Whole-exome sequencing revealed conservation of mutant allele frequencies throughout treatment. Together, these studies demonstrate that re-growth of residual tumors is accompanied by a non-random selection of subclones, that residual tumors surviving AC maintain the same levels of ITH as untreated tumors, and that selection of genomic subclones did not confer the observed chemoresistance.
Transcriptomic, proteomic, and histologic profiling revealed that residual tumors exist in a distinct state characterized by alterations in EMT, metabolic, and cell adhesion programs. This state was reverted as tumors re-grew after discontinuation of AC treatment, indicating that the residual state may be a unique therapeutic window. In silico prediction of drug sensitivity revealed candidate drivers of resistance in the residual tumor state, and pharmacologic targeting identified multiple existing therapies that significantly delayed the regrowth of residual tumors. These data suggest that sequential administration of AC followed by these targeted agents could prolong TNBC responses, which may delay time to recurrence for patients with this highly aggressive disease.
Citation Format: Gloria Vittone Echeverria, Sahil Seth, Zhongqi Ge, Alessandro Carugo, Christopher Bristow, Prabjhot Mundi, Sabrina Jeter-Jones, Xiaomei Zhang, Xinhui Zhou, Aaron McCoy, Shirong Cai, Yizheng Tu, Yuting Sun, Joseph Marszalek, Andrea Califano, William F. Symmans, Stacy L. Moulder, Jeffery T. Chang, Timothy P. Heffernan, Helen Piwnica-Worms. High-resolution barcoding in patient-derived xenografts of triple-negative breast cancer reveals reversible chemoresistance conferred by non-mutational mechanisms abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 212.
Abstract
Osimertinib, a third generation EGFR inhibitor, is a front-line therapy for EGFR mutated non-small lung cancer (NSCLC). The long-term effectiveness of osimertinib is limited by acquired ...resistance. Clinically identified resistance mechanisms include EGFR-dependent mechanisms such as mutations on EGFR that preclude drug binding, and EGFR-independent activation of the MAPK pathway, for instance via activation of alternate RTKs. It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between the multiple resistance mechanisms will restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. SHP2 (Src homology 2 domain-containing phosphatase) is a phosphatase that mediates the signaling of multiple RTKs and is required for full activation of the MAPK pathway. Here we report IACS-13909 - a specific and potent allosteric inhibitor of SHP2 - suppresses the signaling of RTK/MAPK pathway. IACS-13909 potently impedes the proliferation of tumors with a broad spectrum of RTKs as the oncogenic driver. Importantly, in NSCLC models with acquired resistance to osimertinib, IACS-13909 administered as a single agent or in combination with osimertinib potently reduces tumor cell proliferation in vitro and in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFR inhibitor-resistant NSCLC. Currently, a compound that potently inhibits SHP2 has been selected as the clinical development candidate and is undergoing IND-enabling studies with a projected first-in-human target of early 2020.
Citation Format: Yuting Sun, Brooke A Meyers, Sarah B Johnson, Angela L Harris, Barbara Czako, Jason B Cross, Paul G Leonard, Faika Mseeh, Maria E Di Francesco, Connor A Parker, Qi Wu, Christopher A Bristow, Jason P Burke, Caroline C Carrillo, Christopher L Carroll, Qing Chang, Ningping Feng, Sonal Gera, Gao Guang, Justin Kwang-Lay Huang, Yongying Jiang, Zhijun Kang, Jeffrey J Kovacs, Xiaoyan Ma, Pijus K Mandal, Timothy McAfoos, Robert A Mullinax, Michael D Peoples, Vandhana Ramamoorthy, Sahil Seth, Erika Suzuki, Christopher Conrad Williams, Simon S Yu, Andy M Zuniga, Giulio F Draetta, Joseph R Marszalek, Timothy P Heffernan, Nancy E Kohl, Philip Jones. Discovery of IACS-13909, an allosteric SHP2 inhibitor that overcomes multiple mechanisms underlying osimertinib resistance abstract. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C036. doi:10.1158/1535-7163.TARG-19-C036
Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a dismal 5-year survival rate of 8%
1
. Inhibition of oncogenic KRAS (hereafter KRAS*), the ...earliest lesion in disease development that is present in >90% of PDAC, and its signaling surrogates has yielded encouraging preclinical results with experimental agents
2
-
4
. However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies
5
,
6
. Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signaling essential for malignant transformation and tumor maintenance. Insights into the complexity of the functional surfaceome have been technologically limited until recently, and, in the case of PDAC, the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signaling remains largely unexplored. Here, we developed an unbiased, functional target discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which uncovered syndecan-1 (SDC1) as a protein upregulated at the cell surface by KRAS*. Cell surface localization of SDC1 is essential for disease maintenance and progression, where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth. Thus, our study forges a mechanistic link between KRAS* signaling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities.
Abstract
Tumors are comprised of heterogenous populations of tumor cells that rely on both glycolysis and oxidative phosphorylation (OXPHOS) for bioenergy and synthetic processes in support of cell ...proliferation. Over the past few years, we and others have reported that there is a subpopulation of tumors cells that are resistant to standard of care treatment or targeted therapies, and that these so-called persistent tumor cells possess stem cell like properties. Of note, these cells have elevated levels of mitochondria and are dependent on OXPHOS for survival. We have previously disclosed the discovery of IACS-010759, a potent, selective inhibitor of complex I of the electron transport chain, which is orally bioavailable and has excellent PK and physicochemical properties in preclinical species. IACS-010759 is currently in phase I clinical trials in relapsed/refractory AML and solid tumors where initial safety, pharmacokinetics, efficacy and pharmacodynamic impacts on tumor cell biology are being evaluated. As part of the development of IACS-010759, we were interested to explore the impact of the compound to target the persistent tumor cells, in particular by treating AML, TNBC and PDAC PDX models post-chemotherapy with IACS-010759. For all three contexts, IACS-010759 extended progression free survival, consistent with IACS-010759 targeting the recently described metabolically adapted residual tumor cells. For solid tumor indications, we have utilized innovative barcoding and clonal tracking strategies to confirm dependency of a specific subpopulation of tumor cells on OXPHOS. We show that OXPHOS inhibition extends survival and limits AML growth in secondary transplantation by stimulating terminal differentiation of putative stem cells. Taken together, these data provide rationale for multiple Phase II/III clinical trials where IACS-010759 will be used to target persistent tumor cell population and extend survival.
Citation Format: Joseph R. Marszalek, Sahil Seth, Denise Corti, Qi Zhang, Gloria V. Echeverria, Lina Han, Yuting Sun, Jennifer Molina, Sonal Gera, Edward Chang, Tin O. Khor, Mikhila Mahendra, Ningping Feng, Jason P. Gay, Timothy McAfoos, Virginia Giuliani, Xi Shi, Sabrina Jeter-Jones, Sarah Loponte, Chieh-Yuan Li, Christopher A. Bristow, Maria Emilia Di Francesco, Helen Piwnica-Worms, Marina Konopleva, Alessandro Carugo, Andrea Viale, Philip Jones, Timothy P. Heffernan, Giulio F. Draetta. Targeting OXPHOS with IACS-010759 to eliminate standard of care resistant tumor cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2856.
Background
Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non‐small cell lung cancer (NSCLC), characterized by the presence of epithelial and sarcoma‐like components. The ...molecular and immune landscape of PSC has not been well defined.
Methods
Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high‐depth DNA panel, whole‐exome, and RNA sequencing. We describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical outcomes.
Results
In total, 27 canonical cancer gene mutations were identified, with TP53 the most frequently mutated gene, followed by KRAS. Interestingly, most TP53 and KRAS mutations were earlier genomic events mapped to the trunks of the tumors, suggesting branching evolution in most PSC tumors. We identified two distinct molecular subtypes of PSC, driven primarily by immune infiltration and signaling. The Immune High (IM‐H) subtype was associated with superior survival, highlighting the impact of immune infiltration on the biological and clinical features of localized PSCs.
Conclusions
We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with prognosis. IM‐H tumors were associated with favorable recurrence‐free survival and overall survival, highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs.
Overview of clinical characteristics of pulmonary sarcomatoid carcinoma (PSC) cohort and exemplary histopathologic images of three different types of PSC cancers, including Spinfle cell carcinoma, pleomorphic carcinoma, and giant cell carcinoma. Tumors and adjacent normals were subjected to whole‐exome sequencing (N = 18), RNA sequencing (N = 17), and comprehensive cancer panel (N = 21).
Abstract
An important feature of osteosarcoma is relapse which occurs in more than 30% of patients and metastasis to the lungs. It has been revealed that the metastatic ability and resistance to ...chemotherapy might be due to the presence of a subset of cells within the intra-tumorally heterogeneous population. However, tracking the rare genetic subpopulations that play a critical role in cancer recurrence, metastasis and resistance and the lack of a defined in vivo model to recapitulate clonal evolution has been a challenge.
To further understand clonal dynamics and intra-tumoral heterogeneity a new barcoded PDX (OS17) derived cell line was established by stably transducing the cell line with a lentiviral vector-based system. The highly complex barcode library of ten million enabled labelling each of the cells with a unique molecular identifier and clonally tracking more than one million cells in vitro. Following seventeen passages in vitro and transplant for three generations in vivo, flow cytometry, nested PCR and next generation sequencing showed that the barcoded cells retained the sequence in vitro and in vivo suggesting that it was possible to track cell populations and their clonal lineages both at the genomic DNA and RNA level.
The barcoded M17 PDX cells were injected in 25 SCID and NSG mice intratibially to monitor tumor growth and clonally track the cells in both the primary tumors and the lungs. Seventeen (68%) of the mice developed primary tumors. Tumor latency and growth was 61.82 ±34.5 and 51.24 ± 23 days respectively. Seven (35%) of the primary tumor bearing mice had lung metastasis. Limb amputations were performed in 5 mice with 2 surviving the surgery.
The results not only show a diversity in clonal subpopulations between the mice injected on different dates but also the primary tumor and matched lung metastatic samples. An in-depth clonal characterization further revealed a high degree of similarity in the subclonal populations between the lung nodules and the primary tumor samples. In vitro, a proportion of the barcodes were very reduced or lost in the early six passages however, these slowly expanded in the late passages suggesting that in a more favorable environment in vivo, these clones can maintain tumorigenic potential.
These results suggest a clonal evolutionary dynamic model where pre-existing clones have a fitness for persistence and dissemination. This advantage might include long term tumorigenic and proliferative potential and the ability to grow in different micro-environments. Conclusion: It has been demonstrated that the barcoded PDX models have inter and intra-tumoral heterogeneity of osteosarcoma both in vitro and in vivo and can potentially be used in tracking tumor colonization at the primary and metastatic sites. Using this model will therefore advance our understanding of osteosarcoma lung metastasis which is the critical clinical challenge for these patients.
Citation Format: Sylvester Jusu, Sankaranarayanan Kannan, Sahil Seth, Michael D. Peoples, Zhongting Zhang, Wendong Zhang, Zhaohui Xu, Yifei Wang, Xin Zhou, Yizheng Tu, Giuseppe Longo, Michael Roth, Jonathan B. Gill, Richard Gorlick. Comprehensive clonal and molecular profiling of primary tumors and distant lung metastases in an amputation model of osteosarcoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3794.
The PI3K pathway is frequently altered in triple-negative breast cancer (TNBC). Limited cell line and human data suggest that TNBC tumors characterized as mesenchymal (M) and luminal androgen ...receptor (LAR) subtypes have increased incidence of alterations in the PI3K pathway. The impact of PI3K pathway alterations across TNBC subtypes is poorly understood.
Pretreatment tumor was evaluated from operable TNBC patients enrolled on a clinical trial of neoadjuvant therapy (NAT; A Robust TNBC Evaluation fraMework to Improve Survival ClinicalTrials.gov identifier: NCT02276443). Tumors were characterized into seven TNBC subtypes per Pietenpol criteria (basal-like 1, basal-like 2, immunomodulatory, M, mesenchymal stem-like, LAR, and unstable). Using whole-exome sequencing, RNA sequencing, and immunohistochemistry for PTEN, alterations were identified in 32 genes known to activate the PI3K pathway. Alterations in each subtype were associated with pathologic response to NAT.
In evaluated patients (N = 177), there was a significant difference in the incidence of PI3K pathway alterations across TNBC subtypes (
< .01). The highest incidence of alterations was seen in LAR (81%), BL2 (79%), and M (62%) subtypes. The odds ratio for pathologic complete response (pCR) in the presence of
mutation,
mutation, and/or PTEN loss was highest in the LAR subtype and lowest in the M subtype, but these findings did not reach statistical significance. Presence of
mutation was associated with pCR in the LAR subtype (
= .02).
PI3K pathway alteration can affect response to NAT in TNBC, and targeted agents may improve outcomes, particularly in patients with M and LAR TNBC.
Luminal androgen receptor (LAR)-enriched triple-negative breast cancer (TNBC) is a distinct subtype. The efficacy of AR inhibitors and the relevant biomarkers in neoadjuvant therapy (NAT) are yet to ...be determined. We tested the combination of the AR inhibitor enzalutamide (120 mg daily by mouth) and paclitaxel (80 mg/m2 weekly intravenously) (ZT) for 12 weeks as NAT for LAR-enriched TNBC. Eligibility criteria included a percentage of cells expressing nuclear AR by immunohistochemistry (iAR) of at least 10% and a reduction in sonographic volume of less than 70% after four cycles of doxorubicin and cyclophosphamide. Twenty-four patients were enrolled. Ten achieved a pathologic complete response or residual cancer burden-I. ZT was safe, with no unexpected side effects. An iAR of at least 70% had a positive predictive value of 0.92 and a negative predictive value of 0.97 in predicting LAR-enriched TNBC according to RNA-based assays. Our data support future trials of AR blockade in early-stage LAR-enriched TNBC.
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•Enzalutamide plus paclitaxel (ZT) is effective against TNBC•Conventional AR-measuring markers are suboptimal to predict ZT efficacy•AR-responsive gene sets may be tested as predictive markers for ZT efficacy•Various ARness biomarkers of ZT response may provide biological insight
Lim et al. report that for treating triple-negative breast cancers with suboptimal response to adriamycin and cyclophosphamide before surgery, enzalutamide with paclitaxel is effective and safe to induce a response. The authors observe a higher response corresponding with androgen receptor (AR) levels measured by immunohistochemistry or RNA-seq.
Background: Recent advance in massively parallel sequencing technology has enabled identification of a number of novel somatic driver mutations in myelodysplastic syndromes (MDS). While these efforts ...have clearly advanced our understanding of MDS pathogenesis, clinical implication of driver mutations in MDS is less studied.
Methods: We performed whole exome sequencing on bone marrow aspiration samples obtained from 114 consecutive patients with untreated MDS. Exome capture was performed using Agilent's SureSelect V4 and sequencing was conducted using Illumina's HighSeq 2000 platform. Sequencing achieved median 124x coverage for the targeted exons. Mutect and Pindel algorithm were used to call single nucleotide variants (SNV) and small indels against virtual common normal reference. Annotation of high-confidence driver mutations followed the previous publication by Pappaemmanuil et al. (Blood 2013). Clonal heterogeneity of driver mutations was assessed in patients who have 2 or more driver mutations by Pearson's goodness of fit test.
Results: Among the 114 patients with MDS, total 221 high-confidence driver mutations were detected in 39 genes by sequencing. Eighty eight percent (100/114) of the patients were found to have at least one driver mutation. The number of driver mutation ranged from 1 to 5 per case. Commonly detected driver mutations include TET2 (25%), SRSF2 (22%), ASXL1 (20%), RUNX1 (19%), TP53 (12%), SF3B1 (9%), and U2AF1 (9%). As a rare driver mutation, we confirmed ETNK1 p. N244S mutation in 2 MDS patients (2%). This mutation was recently described as a recurrent somatic mutation in atypical CML (Gambacorti-Passerini et al. Blood 2015). Clonal heterogeneity of driver mutations was evaluable in 65 patients (57%). Nineteen patients were found to have clonal heterogeneity in driver mutations (29%).
Among the 114 patients, 61 patients (54%) were treated with HMA therapy. Complete response (CR), partial response (PR), and hematological improvement (HI) was observed in 22 (36%) patients, 4 (7%) patients, and 5 (8%) patients, respectively. Presence of TET2 mutation did not predict response to HMA therapy in this series (P = 0.57) even when we restricted to TET2 mutations with variant allele frequency (VAF) >10%. There was a trend toward poor response to HMA therapy in ASXL1 mutated patients (P = 0.074). None of the other driver mutations were predictive of response to HMA therapy as a sole. However, patients who were found to carry 4 or more driver mutations had significantly poor response to HMA therapy (CR rate 0%) compared to patients with less than 4 driver mutations (P = 0.035). Presence of clonal heterogeneity in driver mutations was not predictive of response to HMA therapy (P = 0.43)
In regards to survival outcome, presence of SF3B1 mutation predicted favorable overall survival (OS, P = 0.02) while TP53, and DNMT3A mutations were associated with worse OS (P < 0.001 and P = 0.02, respectively). Presence of clonal heterogeneity in driver mutations was not prognostic for OS (P = 0.71). Patients who were found to have 4 or more driver mutations were associated with significantly worse OS (P = 0.014). None of the patients with 4 or more driver mutations had SF3B1 mutation. Multivariate Cox proportional hazard regression analysis considering dichotomized variables relevant to IPSS-R classification (absolute neutrophil count < 0.8 x 103 / µ l, hemoglobin < 8 g/dL, platelet count < 50 x 103 / µ l, and bone marrow blast > 10%, and poor or very poor risk cytogenetics), SF3B1 mutation, DNMT3A mutation, TP53 mutation, and the number of driver mutations (≥ 4) revealed that the presence of 4 or more driver mutations (HR = 2.72 95% CI: 1.34-5.53, P = 0.06), platelet count < 50 x 103 / µ l (HR = 4.73, 95% CI: 2.53-8.85, P < 0.001), and TP53 mutation (HR = 3.34, 95% CI: 1.65-6.75, P = 0.001) significantly predicted worse OS.
Conclusion: With the modern sequencing technology, approximately 90% of MDS patients were found to have at least one known myeloid driver mutation. Presence of 4 or more driver mutations in MDS patients predicted poor response to HMA therapy. Multivariate model incorporating mutation profile showed that the presence of 4 or more driver mutations and TP53 mutation status were significantly prognostic in MDS independent of IPSS-R variables. Screening for driver mutations in MDS has clinical impact and mutation profiles should be incorporated into the existing prognostic model.
Daver:ImmunoGen: Other: clinical trial, Research Funding. DiNardo:Novartis: Research Funding.
Abstract
We have seen great advances in our knowledge of the genetic regulation of various cancers in recent years, thanks in large part to large-scale genome sequencing efforts. As we catalogue and ...characterize the genomic aberrations associated with cancers with increasing detail and accuracy, we are faced with the challenge of having to cull bystanders from biologically active drivers and establish relevant disease context in which these drivers are rate-limiting. To address this challenge, we have adapted a loss-of-function screening approach to function in the context of an intact tumor microenvironment using patient-derived tumors that more faithfully recapitulate the human disease compared to established cell lines. Due to the genetic heterogeneity between human tumors, we have integrated independent screening approaches in a flexible platform for the interrogation of patient-derived samples as well as GEM models in exactly the same experimental conditions. The goal of this platform is to identify context-specific genetic vulnerabilities and translate these findings into drug discovery opportunities. As proof of concept, we developed an in vivo loss-of-function screen to systematically interrogate epigenetic dependencies in pancreatic ductal adenocarcinoma (PDAC). The screening system utilizes tumor cells isolated from low-passage xenograft tissue and a lentiviral library of pooled shRNAs targeting 230 “druggable” epigenetic regulators. The custom-designed shRNA library (10 shRNAs per gene) was engineered with unique molecular barcodes that allow quantitation of each clone by deep sequencing. To date, we have completed a total of 5 in vivo screens using diverse PDAC models that have informed on novel epigenetic dependencies. So far, the main limitation for the systematic exploitation of in vivo loss-of-function screens come from the limited number of human cells contributing to tumor establishment in a transplantation setting. The frequency of these tumor initiating cells (TICs) is commonly estimated by limiting dilution assays and may consistently vary between tumor origins. With this in mind, we have integrated in our platform a system based on scrambled barcoded libraries that allow to directly assess the required coverage of screening libraries in each model. Our coverage study demonstrated to be a powerful tool to identify the minimal number of cells/barcode required to sustain a complex library and at the same time a step forward to personalize the in vivo screening patient by patient. We optimized a comprehensive data analytics pipeline and developed a high-throughput validation scheme to triage “hits” that emerge from each screen. The most potent “hits” have been enrolled in both functional and clinico-pathological validation studies to determine the highest priority targets for this devastating disease. Results from these studies will be presented.
Note: This abstract was not presented at the meeting.
Citation Format: Alessandro Carugo, Giannicola Genovese, Sahil Seth, Luigi Nezi, Johnathon L. Rose, Andrea Viale, Piergiorgio F. Pettazzoni, Angelo Cicalese, Daniela Bossi, Wantong Yao, Jason B. Fleming, Luisa Lanfrancone, Timothy P. Heffernan, Giulio F. Draetta. Identification of epigenetic modifiers able to suppress growth of pancreatic ductal adenocarcinoma: A patient-oriented in vivo functional platform. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1701. doi:10.1158/1538-7445.AM2015-1701
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