bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA15: Lung cancer genomics
Authors: Gadgeel Shirish M.
Published: March 2017

Lung cancer remains the most common cause of cancer related deaths in the United States. The primary reason for the high mortality rate is the advanced stage of the disease at the time of diagnosis. Racial disparities in incidence and mortality have been observed in the United States, with higher rate among African-Americans, particularly males.

In recent years genetic alterations that bestow a proliferative and survival advantage, so called ‘driver' genetic alterations, have been identified in a subset of cancers including Non-Small Cell Lung Cancer (NSCLC). Molecular changes resulting from these genetic alterations can be targeted for therapeutic benefit and such targeted therapy has become standard of care for the management of NSCLC patients. These data have generated an interested in assessing and understanding lung cancer genomics. Several studies have been conducted and results of these studies have allowed the characterization of lung cancer into genomically distinct categories that may have implications for tumor biology and possibly for cancer therapeutics.

Racial and ethnic variations in the incidence of specific ‘driver' genetic alterations have been observed. Thus the incidence of EGFR (epidermal growth factor receptor) mutation positive NSCLC is higher in Asian population compared to North American population. Such differences have not been observed for ALK (anaplastic lymphoma kinase) gene rearrangement positive NSCLC. These observations have generated an interest in evaluating lung cancer genomics to explain the observed racial differences in both incidence and mortality. Ongoing efforts will attempt to define racial and ethnic differences, if any in lung cancer genomics and the implications of the same.

Citation Format: Shirish M. Gadgeel. Lung cancer genomics. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA15.
Abstract IA16: Lung cancer, immunotherapy and health disparities
Authors: Adjei Alex A.
Published: March 2017

In recent years, there has been a deeper understanding of the mechanisms of immune evasion by cancer cells. This has led to the development of a number of immune checkpoint inhibitors for cancer therapy. The first inhibitor to be approved was ipilumumab, a monoclonal antibody that works to activate the immune system by targeting CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), a protein receptor that downregulates the immune system. Ipilimumab inhibits CTLA4, which is important for dampening T cell responses at the priming phase in lymph nodes, and is approved for the therapy of malignant melanoma. The role of checkpoint inhibitors in cancer therapy has blossomed over the last couple of years with the advent of PD1/PDL1 inhibitors. These agents are currently approved for the therapy of NSCLC, melanoma, renal cell carcinoma, bladder cancer hodgkins lymphoma and head and neck cancer.

The approved agents are nivolumab, pembrolizumab and atezolizumab. A number of other checkpoint inhibitors are in development. Lung cancer mortality is disproportionately high in minority populations. Pembrolizumab and nivolumab are approved for the second line therapy of non-small cell lung cancer and combinations of PD-1/PD-L1 inhibitors and CTLA4 inhibitors such as nivolumab/ipilimumab are being evaluated for small cell and non-small cell lung cancer.

As always, a number of clinical trials have been done with these agents, but these have included very few minority patients. The clinical effects and unique toxicities of these agents will be discussed, as will their cost. Implications of these new treatment modalities for minority and underserved populations with lung cancer will also be discussed.

Citation Format: Alex A. Adjei. Lung cancer, immunotherapy and health disparities. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA16.
Abstract IA21: Cancer and the LGBT community
Authors: Matthews Alicia K.
Published: March 2017

In response to the clear and persistent trends the elimination of cancer-related health disparities among racial/ethnic minorities has been a national public health priority. For the first time Healthy People 2020, the nation's roadmap for improving the health of Americans, also includes sexual minorities as population of priority. Although precise data on cancer rates among lesbians are lacking, evidence suggests that sexual minority status may contribute to excess risk for the development of certain types of cancers, including breast cancer, anal cancer, lung cancer and cancers associated with HIV/AIDS. The causes of these disparities are complex and likely influenced by the same factors that drive cancer disparity rates among African American and other underserved populations. These factors include poor continuity of care; socioeconomic factors, such as lack of adequate insurance coverage; medical mistrust; cultural and emotional factor; and providers' unintentional bias and inadequate cultural competency. The purpose of this presentation is to discuss risk factors for cancer disparities among LGBT individuals and to describe existing cancer risk reduction interventions targeted toward this community.

Citation Format: Alicia K. Matthews. Cancer and the LGBT community. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA21.
Abstract IA25: The Cancer Genome Atlas: a primer on 2.5 PB of high quality data
Authors: Zenklusen Jean C.
Published: March 2017

Although The Cancer Genome Atlas (TCGA) has produced an unprecedented amount of data molecularly characterizing thirty-two tumor types, the usability of the data has been restricted by download model. The Genomics Data Commons (GDC) is a new database for retrieval and query of all NCI genomic-level data, allowing the user to identify areas of interest and download the information on just those segments (BAM slicing). All the data contained in the GDC will be mapped to the genome (aligned) and variations on the sequence called in a uniform fashion. In future releases, the GDC will incorporate a variety of analytical tools, obviating the need to download the raw data in order to analyze it. However, the ethnic diversity represented in the data is sparce; a new initiative by the NCI will try to bridge that deficiency by targeting accrual of minorities (as well as early onset cases) in five different tumor types.

Citation Format: Jean C. Zenklusen. The Cancer Genome Atlas: a primer on 2.5 PB of high quality data. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA25.
Abstract IA28: Colorectal cancer screening and diagnostic services for urban and rural safety-net-settings
Authors: James Aimee S.
Published: March 2017

Background:

Colorectal cancer (CRC) is a leading cause of cancer mortality and a relatively common cancer diagnosis in the United States. CRC screening is effective and cost-effective for reducing mortality. Screening rates for CRC, while increasing, are lower than for many other cancer screening tests. There is a clear benefit to early detection. Early stage CRC is often treatable, with five year survival rates over 90%. Later stage CRCs are associated with poorer outcomes. Furthermore, CRC Screening is notable in its ability to prevent cancers through the detection and removal of pre-cancerous polyps. There are several USPSTF-recommended options for screening.

Cancer health disparities are evident in CRC. Under- or un-insured and lower income adults generally have lower rates of screening, later stage at diagnosis, and poorer survival outcomes. Many of these adults seek care in the healthcare “safety-net”, including federally qualified health centers. Such settings themselves are often under-resourced.

Methods:

Our team has studied CRC screening from multiple perspectives in the safety-net setting across several studies. Most recently, we conducted a cluster randomized trial to promote CRC screening across several rural and urban health centers. The trial applied principles of community-based participatory research and intervened at the patient and provider/clinic levels. Implementation outcomes were monitored and recorded.

Findings:

Implementation of screening and screening programs in safety-net settings face unique challenges and researchers need to be aware of the context in which these patients are seeking and receiving their healthcare. Given the high cost of diagnostic follow-up for positive FOBT/.FIT, and the costs of colonoscopy even for screening, many safety-net patients face barriers to screening and follow-up.

This talk will explore the cross-section of health disparities research and implementation and dissemination research, highlighting data from community-engaged research and community-clinical-academic partnership in the Program for the Elimination of Cancer Disparities, an NCI-funded community networks program center.

Citation Format: Aimee S. James. Colorectal cancer screening and diagnostic services for urban and rural safety-net-settings. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA28.
Abstract IA41: Emerging Issues in Cancer Screening for Racial and Ethnic Minorities
Authors: Halbert Chanita Hughes
Published: March 2017

Cancer screening plays an important role in early detection; detecting cancer in an early stage has important implications for cancer health disparities. Considerable efforts have been made to increase access to early detection services among racial and ethnic minorities in order to improve cancer outcomes in these populations. However, our recent work has shown that racial disparities in cancer screening continue to exist. For instance, about 40% of women in our national random survey of cultural considerations in cancer screening were not up-to-date with mammography guidelines. Our other work with a community-based sample of African American men demonstrated that informed decision-making about PSA testing may be low. Fifty-seven percent of men reported having a PSA test during the past year, but none of the variables that are important to informed decision-making were associated with having annual screening. With respect to lung cancer screening, our recent qualitative research demonstrated that patients have limited discussions with providers about the benefits and limitations of lung cancer screening and had difficulty recalling receipt of information about screening, even though many decided to have low dose computed tomography (LDCT). This may be because of limited knowledge about screening guidelines and low enthusiasm and commitment to LCDT among providers. Providers relied on clinical reminders from the electronic health system to remind them to assess patients for eligibility for LDCT and offer screening. Provider referral to smoking cessation programs was also limited. Provider referral to smoking cessation programs, and delivery of this service, is especially important among high-risk smokers who are candidates for LCDT. Using data from the National Lung Screening Trial (NLST), our research demonstrated that current smokers have an increased risk of lung cancer and all-cause mortality compared to former smokers regardless of randomization to LCDT or the control condition. In addition, smoking abstinence for seven years was associated with a 20% reduction in lung cancer mortality among those screened with chest radiograph. Screening with LCDT and smoking abstinence for 15 years had the greatest mortality risk reduction. African Americans were under-represented in the NLST; therefore, greater efforts are needed to disseminate and implement lung cancer screening in more diverse health care facilities.

Citation Format: Chanita Hughes Halbert. Emerging Issues in Cancer Screening for Racial and Ethnic Minorities. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA41.
Abstract A16: Establishment and characterization of CCGL007, a novel human chronic lymphocytic leukemia cell line
Authors: Kuo Ching-Chuan , Chen Chih-Cheng , Huang Chih-Hsiang , Li-Mei Lin
Published: March 2017

Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. However, lack of immortalized cell line representative of the CLL disease has hampered a full understanding of disease pathogenesis and development of novel therapeutic agents for treatment. There were very few representative CLL cell lines are available now. To this end, we have tested different culture condition with addition of growth factor supplements to generate CLL cell lines from highly purified peripheral blood B cells of CLL patients. Recently, we have successfully established a new CLL cell line, named CCGL007. CCGL007 cells grow as suspension in liquid culture. Surface marker analysis with a panel of monoclonal antibodies revealed that CCGL007 cell line expresses B cell markers. The chromosomal, immunophenotypic, molecular biologic characteristics, and in vivo tumorigenesis potential of CCGL007 is under investigation. We have used this cell model to test the efficacy of selected standard chemotherapy drugs and new therapeutic agents, such as ibrutinib and several novel in-house BTK inhibitors, against CLL cell growth, and CCGL007 represents as a suitable preclinical model for testing pharmacological agents.

Citation Format: Ching-Chuan Kuo, Chih-Cheng Chen, Chih-Hsiang Huang, Lin Li-Mei. Establishment and characterization of CCGL007, a novel human chronic lymphocytic leukemia cell line. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A16.
Abstract A29: Evaluating the dynamics of epigenetic changes conferring targeted cancer drugs resistance in tumor xenograft propagation model
Authors: YOU REN-IN , CHEN CHUN-SHAN , CHEN CHUN-YI , Agustina Simarmata
Published: March 2017

Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancers. Although selective targeted therapy by kinase inhibitors have been emerged as important therapeutic agents in the treatment of a variety of human malignancies. Cancer cells become resistant to targeted cancer drugs are a major obstacle to successful cancer treatment. A major mechanism of resistance is the presence of a small sub-population of cancer cells have genetic changes, aberrant epigenetic modifications and activation of alternative signaling pathways by modifying the expression of several downstream effectors contribute to the acquisition of cancer target drug resistance. To dissect the alternate pathways exist to confer targeted cancer drugs resistance, the kinase inhibitors resistant cancer cells were established by continuous culture in increasing doses. Furthermore, the resistant cancer cells were inoculated into SCID mice and then tumors were excised and serially transplanted into additional mice for propagation. By in vivo serial dilution tumor-propagating assay, the established resistant cancer cell lines and xenografts were characterized using cell growth kinetics, targeted drug sensitivity and tumorigenicity. The gene overexpression and shRNA knockdown approaches were employed to investigate the mechanism of bypassing target gene effects from propagating cells in vitro. Confirmation of target drug sensitivity of drug resistant transfectants may allow for the identification of new therapeutic targets or prognostic biomarkers of cancer drugs response. The resistance-related genes having measurable effects in vitro and in vivo demonstrate that the established model in this study is appropriate for validation of genes that responsible for targeted drug resistance.

Citation Format: REN-IN YOU, CHUN-SHAN CHEN, CHUN-YI CHEN, Simarmata Agustina. Evaluating the dynamics of epigenetic changes conferring targeted cancer drugs resistance in tumor xenograft propagation model. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A29.
Abstract A31: Proteomic characterization of stromal contribution to tumor using patient-derived xenografts
Authors: McDermott Jason E. , Liu Tao , Petyuk Vladislav , Smith Richard , Rodland Karin
Published: March 2017

Patient-derived xenografts (PDXs) are an important and powerful tool to study many types of cancer and provide valuable insight into potential drug response and development of resistance. Due to the differences in tissue lineage PDXs also allow the dissection of stromal contribution to the tumor that is not easily obtainable from examination of the original tumor itself. We have applied mass-spectrometry enabled proteomics, phosphoproteomics, and RNAseq to compare primary metastasis, and PDXs derived from several metastatic sites from the same original tumor which was a colorectal adenocarcinoma.

Comparing our results with a large-scale proteomic characterization of tumors performed under the clinical tumor analysis consortium (CPTAC) shows that the original metastasis, and PDXs from different sites, are significantly similar, regardless of metastasis site. Proteomic profiles of these samples are enriched in proteins expressed in the tissue of origin, rather than the site of metastasis. Pathway analysis from proteomics revealed enrichment in complement cascade, extracellular matrix receptors, and focal adhesion. These were different than the pathways indicated by the transcriptomics, which included cell cycle, focal adhesion, and MAP signaling, but not complement or extracellular matrix.

We found in the case of complement and focal adhesion the original metastasis sample was very different from the PDX samples, if we only considered human protein contributions. Considering mouse proteins we found that the mouse stromal contribution complemented the human tumor contribution in the PDXs, aligning the functional analysis in both types of samples. Combining these results with subsequent analysis of driver mutations revealed that the proteomic contribution of stroma was as high as 40%. We have extended these observations to additional pairs of clinical tumor specimens and paired PDXs, including different tumor types. In all cases, there is greater similarity among the same sample type (resected tumor, metastatic lesion, or PDX) than between different sample types from the same patient.

Citation Format: Jason E. McDermott, Tao Liu, Vladislav Petyuk, Richard Smith, Karin Rodland. Proteomic characterization of stromal contribution to tumor using patient-derived xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A31.
Abstract B07: Screening of patient-derived carcinoma cells and animal models identifies transcription as target in pancreatic cancer.
Authors: Khazak Vladimir , Skobeleva Natalia , Beglyarova Natalia , Bobrov Egor , Zhou Yan , Jablonski Sandra A. , Weiner Louis M. , Paz Keren , Astsaturov Igor
Published: March 2017

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy that affects 44,000 individuals yearly in the US. With almost 90% lethality even when diagnosed prior to metastasis, there is an urgent unmet medical need for new therapies or better matching of existing therapies to patients. To address this emergency, we first had developed a panel of new physiological models for study of PDAC, rapidly expanding surgical PDAC tumor samples in culture with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). Using this panel, we evaluated sensitivity to a large panel of existing drugs. Only a small minority of agents were cytotoxic in vitro in a significant number of independent PDAC models. Among these, transcriptional repressors were predominated. From a short list of drugs not previously used in PDAC, triptolide, a covalent inhibitor of the ERCC3, a bifunctional regulator of transcription and DNA repair, was most consistently effective in vitro and highly effective in vivo, causing prolonged complete regression in multiple PDX models. Triptolide is a natural product compound from Chinese medicinal plant Tripterygium wilfordii, and it was found to be the most active agent in the screen. Importantly, triptolide showed superior activity in MYC-amplified PDX models, suggesting a critical role for ERCC3 in this subset. Triptolide elicited rapid and profound depletion of MYC oncoprotein, a transcriptional co-factor for ERCC3. Expression of ERCC3 was MYC-dependent, while resistance to triptolide was associated with elevated ERCC3 and MYC expression. These findings provide preclinical evidences for transcriptional vulnerability in PDAC via ERCC3 targeting and a new mechanistic approach for disruption of MYC-dependent pancreatic cancers.

Citation Format: Vladimir Khazak, Natalia Skobeleva, Natalia Beglyarova, Egor Bobrov, Yan Zhou, Sandra A. Jablonski, Louis M. Weiner, Keren Paz, Igor Astsaturov. Screening of patient-derived carcinoma cells and animal models identifies transcription as target in pancreatic cancer.. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B07.
Abstract B20: Development of metastatic patient-derived xenografts (PDXs) for accurate assessment of anti-metastatic therapeutics in pre-clinical settings
Authors: Ice Ryan , Kiseleva Anna , Loskutov Yuriy , Smolkin Matthew , Salkeni Adham , Hazard Hannah , Layne Ginger , Pugacheva Elena
Published: March 2017

Background: Although advances in treating early stage breast cancers have increased the overall survival rate, once the disease has metastasized treatment options subside to palliative care. The limited access to metastatic biopsies and disease-relevant pre-clinical models to test new therapeutics targeted against advanced metastatic cancers limits progress and translation of investigational therapeutics to the clinic.

Methods: To address this deficiency we developed a collection of metastatic patient derived xenograft models via direct transplantation of metastatic biopsy or residual surgical material in immunocompromised mice. We successfully collected and established triple negative as well as ER/PR positive patient xenografts which are available for collaborative research. We further characterized and utilized the PDXs to assess the efficacy of new combination therapy to treat distant metastases.

Results: The efficacy of Aurora A kinase inhibition by small molecule inhibitor MLN8237 (Alisertib) as monotherapy and in combination with microtubule targeting drug, eribulin, on different stages of metastasis and potential mechanisms of its action was defined. Our work using PDX models indicates that Alisertib does not limit growth of the primary tumor. These findings are similar to the results of clinical trials with Alisertib in breast cancer. Importantly, we found that Alisertib dramatically decreases growth of the established metastases and prevents further dissemination via inactivation of AKT and activation of cytotoxic autophagy. Combination of Alisertib with eribulin led to a synergistic decrease in metastases to distant organs and provided additional local control of mammary tumor growth.

Conclusion: Metastatic PDX models provide new, accurate assessment of anti-metastatic regiment's efficacy. MLN8237 plus eribulin combination shows synergistic inhibition of metastatic spread, growth of established metastases and prolongs overall survival. Future clinical trials are needed to further test this regiment in clinic to improve survival of metastatic cancer patients.

Citation Format: Ryan Ice, Anna Kiseleva, Yuriy Loskutov, Matthew Smolkin, Adham Salkeni, Hannah Hazard, Ginger Layne, Elena Pugacheva{Authors}. Development of metastatic patient-derived xenografts (PDXs) for accurate assessment of anti-metastatic therapeutics in pre-clinical settings. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B20.
Abstract B46: Inhibition of STAT3 enhances the radiosensitizing effect of Temozolomide in vitro and in vivo: Validation using patient-derived glioblastoma model
Authors: Han Tae Jin , Choi Eun Jung , Cho Bong Jun , Song Sang Hyuk , Paek Sun Ha , Kim In Ah
Published: March 2017

Background and purpose: Despite aggressive treatment with radiation therapy plus temozolomide (TMZ), the prognosis for glioblastoma remains poor. We investigated the potential of targeting signal transducer and activator of transcription-3 (STAT3) to improve the therapeutic outcome of glioblastoma.

Material and methods: We evaluated the preclinical potential of a STAT3 inhibitor, Cpd188 combined with temozolomide and radiation in vitro assays using two established glioblastoma cell lines (U251, U87) and two patients-derived glioblastoma cell lines (GBL12, GBL28) and in vivo studies using nude mice bearing intracranial U251 xenografts.

Results: Cpd188 potentiated the radiosensitizing effect of TMZ in U251 cell which has high levels of p-STAT3 expression. Increased radiosensitizing effects of TMZ were associated with impaired DNA damage repair, apoptosis and the reversion of epithelial-mesenchymal transition (EMT). Cpd188 delayed in vivo tumor growth both alone and in combination with radiation and TMZ. We also confirmed the radiosensitizing effect of Cpd188 of GBL28 cell which was originated from a patient with high level of STAT3 expression and unmethylated MGMT.

Conclusion: Targeting STAT3 using Cpd188 could be a viable therapeutic approach to improve the outcome of current standard therapy for glioblastoma patients having high p-STAT3 expression regardless of MGMT methylation status.

*Work supported by the grant (#2013R1A1A2074531) from the Ministry of Science, ICT & Future Planning to In Ah Kim

Citation Format: Tae Jin Han, Eun Jung Choi, Bong Jun Cho, Sang Hyuk Song, Sun Ha Paek, In Ah Kim{Authors}. Inhibition of STAT3 enhances the radiosensitizing effect of Temozolomide in vitro and in vivo: Validation using patient-derived glioblastoma model. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B46.
Abstract IA01: The proteogenomics of breast cancer patient-derived xenografts
Authors: Ellis Matthew J.
Published: March 2017

Next generation DNA sequencing (NGS) has provided vast quantities of data on the genomic landscape of common solid malignancies yet the discovery yield in terms of new treatment approaches has been modest. At the most fundamental level this is because we still lack a deep understanding of how complex somatic changes in the cancer genome drive the cellular phenotypes associated with cancer lethality. Our recent work in breast cancer has demonstrated that discovery mass spectrometry-based proteomics of genome annotated clinical and PDX samples (“proteogenomics”) elucidates functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies potential therapeutic targets. The advantages of patient-derived xenografts (PDX) as a source of material for proteogenomics are readily evident. Larger amounts of tumor protein required for mass spectrometry can be obtained, sample ischemia can be controlled and drug perturbation studies to study drug resistance can be easily conducted. However we still have to firmly establish that the proteome of the progenitor human tumor strongly correlates with the proteomic characteristics of the tumor that eventually emerges after engrafting into immunocompromised mice. This is critical as from the genomic perspective, engraftment does represent an evolutionary bottle neck that, at least in some cases, alters tumor clonality. The discovery potential as well as limitations of PDX for the emerging area of proteogenomics will therefore be discussed.

Citation Format: Matthew J. Ellis. The proteogenomics of breast cancer patient-derived xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA01.
Abstract IA06: Patient-derived orthotopic xenografts (PDOX): Better mimic the patient than subcutaneous xenografts
Authors: Hoffman Robert M.
Published: March 2017

The majority of human solid tumors do not metastasize when grown subcutaneously in immunocompromised mice; this includes patient-derived xenograft (PDX) models. However, orthotopic implantation of intact tumor tissue can lead to primary tumor growth and metastasis that mimics that seen in patients. These patient-derived orthotopic xenograft (PDOX) models have a long history and better recapitulate human cancer than PDX models.

Citation Format: Robert M. Hoffman. Patient-derived orthotopic xenografts (PDOX): Better mimic the patient than subcutaneous xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA06.
Abstract IA07: Patient-derived tumor xenografts for genotype-drug response correlations in colorectal cancer
Authors: Trusolino Livio
Published: March 2017

Ten years after completion of the Human Genome Project, genetic alterations with causative roles in cancer have been identified. Inhibitors that target “druggable” mutant gene products have been developed. Finally, a number of these drugs have entered the clinic and are now used in patients.

Some fundamental issues need to be addressed before the informative potential of genome- wide molecular surveys is translated into clinical benefit. First, given the heavy mutational load accrued during neoplastic progression, driver alterations are difficult to distinguish from passenger events. Second, next-generation approaches are likely to identify previously neglected small subsets of very rare variants, which requires population-scale studies for statistically solid genotype/response correlations. Third, not always does the presence of an oncogenic driver predict response. Therefore, treatment paradigm may not be decided on the sole basis of the mutational status of a single gene with potential cancer-causing function, but rather on the basis of the heterogeneous context in which that mutation is found (“precision medicine”).

All these challenges also apply to metastatic colorectal cancer (mCRC). Less than 20% of mCRC patients respond to anti-EGFR antibodies “the gold standard targeted therapy”, which calls for the identification of novel predictive biomarkers and suggests that uncharacterized drivers other than EGFR can sustain the growth of different CRC subsets. The categorization of tumor subpopulations featuring specific driver lesions, the validation of such lesions as targets, and the need for discrimination between “actionable” opportunities and those with weak clinical transferability require reliable preclinical models. The scope of our research is to refine genetic, mechanistic and therapeutic annotation of mCRC subsets using predictive in vivo models – namely, large collections of molecularly annotated patient-derived tumorgrafts as a means to systematically increase the success rate of rationally based clinical trials that emanate from preclinical findings.

Citation Format: Livio Trusolino. Patient-derived tumor xenografts for genotype-drug response correlations in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA07.
Abstract IA15: Promise and challenges of pediatric cancer PDX models
Authors: Houghton Peter J. , Kurmasheva Raushan T.
Published: March 2017

The Pediatric Preclinical Testing Program (PPTP) has evaluated almost 97 single agents and several combinations over the last 10 years. A total of 89 xenograft models that encompass solid tumors, brain tumors, and acute leukemias have been used as a screen to identify novel agents that could be accelerated for clinical trial. With few exceptions, all models were directly established in mice from patient biopsies, and approximately half of the models were established from patients who were refractory or had relapsed.

Expression analysis showed that tumor models clustered with their appropriate clinical histotype, and exome sequencing showed mutation frequency and identity to be similar to published genomic data for patient cancers. The models accurately identified known active agents that are used as standard of care therapy for solid tumors and leukemias, thus validating the models.

Criteria for assessing response similar to clinical criteria were developed. Of the 97 agents tested, twenty-four signaling inhibitors (ligand or receptor binding antibodies, kinase inhibitors etc.) were evaluated. With the exception of inhibitors of Aurora kinase A, and Polo-like kinase 1, the overall objective response rate (ORR) was <2%. The low response rate is probably an accurate reflection of likely ORR in clinical trials, as the models identified selumetinib in an astrocytoma with BRAF (V600E) mutation, dasatinib in a Ph+ ALL, sorafenib in a Flt3 mutant ALL, and crizotinib in an ALK mutant neuroblastoma.

The models identified several cytotoxic agents as having broad-spectrum antitumor activity (eribulin, alisertib, PR-104), with small molecule and antibody conjugated antimitotic agents showing high-level activity in many models (eribulin in sarcoma and ALL, glembatumab in osteosarcoma). The major issue is that the models overpredict drug activity due to tolerance of the host (mouse) compared to patients. Thus, it is imperative to adjust dose/schedule to accurately reproduce clinical exposures.

Another issue to be addressed is whether the models adequately encompass genomic and epigenomic heterogeneity. With increasing evidence of molecular subtypes within histotypes previously considered as relatively homogeneous, it is clear that additional models need to be established. We have analyzed 2134 tumor/drug studies undertaken as part of the PPTP to determine whether alternative experimental designs can be used that would allow an increased genomic diversity to be interrogated using current resources.

Citation Format: Peter J. Houghton, Raushan T. Kurmasheva. Promise and challenges of pediatric cancer PDX models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA15.
Abstract IA16: Patient-derived xenograft models in glioblastoma
Authors: Seoane Joan
Published: March 2017

One the most important challenges in the treatment of cancer is its evolving genomic intratumor heterogeneity. Tumors are composed of assortments of cells with subclonal genomic alterations that evolve following Darwinian selection. Glioblastoma (GBM) is a prototypical heterogeneous tumor and still little is known about how intratumor heterogeneity influences the progression of GBM and, most importantly, determines the response to treatments and tumor relapse. The study of the spatial and temporal genomic architecture of GBM is essential to understand the biology and improve the treatment of this dismal disease. Through the study of primary and relapsed tumors and patient-derived xenograft models (PDX) of GBM, we are studying the genomic subclones emerging after treatment since these subclones might be enriched in genomic alterations that confer a selective advantage and resistance to treatment. Putative genomic alterations involved in tumor resistance to treatment are further studied and validated through PDX models.

Citation Format: Joan Seoane. Patient-derived xenograft models in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA16.
Abstract IA22: Studying drug resistance through PDX models
Authors: Scaltriti Maurizio
Published: March 2017

Emergence of drug resistance is the main limitation for a durable response to therapy. The mechanisms of such resistance need to be uncovered in order to identify those patients that are more likely to respond and/or develop novel strategies to overcome tumor adaptation to therapy.

Patient-derived xenografts can be established from patients at any stage of their treatment. However, samples collected before the exposure to the pharmacological pressure (therapy-naïve) and tumors from patients that progressed to therapy after an initial response (acquired resistance) are preferable.

Of particular interest are the models derived from outliers; that are either patients unexpectedly refractory to a given therapy (e.g. BRCA-mut tumors not responding to PARP inhibitors or HER2-positive tumors not responding to anti-HER2 agents) or patients that exhibited an exceptional response (magnitude/durability) to specific targeted agents.

There are at least two advantages in using patient-derived material for this kind of studies. The availability of virtually limitless tissue allows deep genomic and proteomic analysis of tumor cells that supposedly resemble the clinical scenario. Moreover, the possibility to perpetuate these tumors is crucial to confirm the resistance phenotype and test novel and more efficacious therapeutic options.

In my presentation I will include several examples of how patient-derived models have helped demonstrating the genuineness of previously hypothesized mechanisms of resistance to targeted therapy and have been instrumental to test combinatorial strategies that resulted in remarkable antitumor activity. Furthermore, I will show that patient-derived models can also serve as tools to test novel “smart” drug delivery systems.

Citation Format: Maurizio Scaltriti. Studying drug resistance through PDX models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA22.
Abstract IA28: Innovative PDX models for studying immunotherapy of cancer
Authors: Sanmamed Miguel F.
Published: March 2017

PDX models are limited by the absence of a complete and functional immune system. Overwhelming evidence now exists to suggest that immune cells play an integral role in the development and maintenance of tumors. Without a functional immune system, PDX models cannot reflect the dynamic processes of tumor-immune surveillance and immune-mediated editing, limiting the translation of antitumor results obtained in these models. Another important consequence of lacking an immune system is the impossibility to test in these models anticancer drugs that directly target immune cells. To overcome these important limitations, PDX models with human immune systems are needed. There are different approaches to enrich PDX models with human immune cells: engrafting human peripheral blood mononuclear cells, engrafting hematopoietic stem cells, or engrafting primary patient-derived tumor xenografts with human tumor infiltrating lymphocytes. All these alternatives have different strengths and weaknesses that are important to know for obtaining preclinical results that are meaningful for clinical translation.

Citation Format: Miguel F. Sanmamed. Innovative PDX models for studying immunotherapy of cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA28.
Abstract PR01: Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids
Authors: Muthuswamy Senthil K.
Published: March 2017

There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

This abstract is also being presented as Poster B10.

Citation Format: Senthil K. Muthuswamy. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR01.
Abstract PR04: Integration of CRISPR-Cas9, RNAi and pharmacologic screens identify actionable targets in a rare cancer
Authors: Hong Andrew L. , Tseng Yuen-Yi , Cowley Glenn , Jonas Oliver , Cheah Jaime , Doshi Mihir , Kynnap Bryan , Oy Coyin , Keskula Paula , Kryukov Gregory , Cima Michael , Langer Robert , Schreiber Stuart , Root David , Boehm Jesse , Hahn William
Published: March 2017

Loss-of-function screening using RNAi technologies over the past decade and more recently with CRISPR-Cas9 technologies have been applied to well-established cancer models. We asked if minimally passaged cancer models would tolerate such screening modalities, particularly perturbations focused on actionable drug targets. We have established a patient derived model, CLF-PED-015-T, as a proof of concept to test this question. After validating that the cell line retains the major genomic, transcriptomic and tumorigenic properties of the tissue it was derived from, we then performed systematic genetic screens using both CRISPR-Cas9 and RNAi to identify potentially actionable vulnerabilities. We then overlapped this with pharmacologic screens. We identified dependencies to CDK4 and XPO1 that spanned all three screens. These dependencies have subsequently validated in an in vivo model. These results suggest use of such technologies at early stages of patient derived model development is feasible.

This abstract is also being presented as Poster B14.

Citation Format: Andrew L. Hong, Yuen-Yi Tseng, Glenn Cowley, Oliver Jonas, Jaime Cheah, Mihir Doshi, Bryan Kynnap, Coyin Oy, Paula Keskula, Gregory Kryukov, Michael Cima, Robert Langer, Stuart Schreiber, David Root, Jesse Boehm, William Hahn. Integration of CRISPR-Cas9, RNAi and pharmacologic screens identify actionable targets in a rare cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR04.
Abstract A02: A pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors
Authors: Xin Gang , Schauder David , Jiang Aimin , Joshi Nikhil , Cui Weiguo
Published: March 2017

Despite the remarkable success in treating hematological malignancies, adoptive cell transfer (ACT) still faces several challenges in treating solid tumor. The main stumbling blocks include insufficient quantity of tumor-specific T cells for transfer, impaired migration of transferred T cells into the tumor and the immunosuppressive microenvironment within the tumor. To overcome these problems, we designed an innovative approach that not only overcomes immunosuppression, but also induces robust anti-tumor T cell responses in the tumor. We first genetically engineered dual-specific CD8 T cells that can recognize both a tumor associated antigen and a bacterial antigen in vitro. Then, we treated tumor-bearing mice with ACT using a small number of the dual-specific CD8 T cells. This was accompanied by intratumoral injection of a low dose of the bacteria, which was sufficient to break local immunosuppression. The dual-specific CD8 T cells expanded robustly and migrated to the tumor bed in response to the infection. At the same time, the second TCR of these effector CD8 T cells recognized tumor antigen and executed effector function, causing tumor regression. As a result of this enhanced anti-tumor effects, 60% of the treated mice successfully eradicated their solid tumor at the primary site. Our approach not only overcomes immunosuppression, but also recruits robust anti-tumor T cell responses to the tumor. Overall, our study harnesses the power of multiple arms of the immune system with promising translational value, which can be used to target many types of solid tumors.

Citation Format: Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui. A pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A02.