bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3070: Discovery of novel potent allele-selective KRAS-G12C covalent inhibitors stemming from DNA-encoded library
Authors: McCort Gary , Arrebola Rosalia , Calvet Loreley , Ronan Baptiste , Vergne Fabrice , Duffieux Francis , Rak Alexey , Meaux Isabelle , Papin David , Fassy Florence , Delorme Cecile , Matthieu Magali , Nicolas Jean-Paul , Marcireau Christophe , Steier Valerie , Abecassis Pierre-Yves , Czepczor Valerie , Thomson Heather A. , Hupp Christopher D. , Guilinger J.P. , Zhang Ying , Keefe Anthony D. , Cuozzo John W. , Liu Julie , Debussche Laurent
Published: August 2019

From a screening of 27 106 covalent DNA-encoded compound library, a novel KRAS G12C chemical series has been identified. Original hit series compound displayed low µM covalent binding activity to KRAS G12C under GDP form associated with a k(inact)/Ki of 1,03 M-1.s-1, a stable electrophilic covalent warhead (T1/2 in 5mM GSH > 24h), +12°C stabilization Delta Tm in DSF assay and 3 µM IC50 value in GEF assay, while no detectable covalent binding to KRAS G12C under GTP form and to KRAS WT or KRAS G12D under GDP form. From 3 µM, it also induced significant pERK inhibition in H358 KRAS-G12C but not in A549 KRAS G12S NSCLC cell lines. Unique binding mode to SII pocket was demonstrated by Xray crystallography. Multi-parametric and structural biology guided chemical optimization yielded potent KRAS G12C lead compounds which combine k(inact)/Ki > 500 M-1.s-1, Delta Tm=20°C, 10 nM range pERK IC50 values with correlated direct KRAS G12C selective covalent modification. They also exhibited 100 nM range KRAS G12C allele-specific anti-proliferative activity and triggered significant apoptosis induction. In vivo treatment of mice bearing H358 tumour xenografts through oral route with optimized candidates showed a marked and prolonged inhibition of both pERK and DUSP6 mRNA as well as consistent direct KRAS-G12C covalent modification as evidenced by LC-MS in tumor samples. Altogether, these data demonstrate the power of DNA-encoded library approach to deliver potential drug candidates with selective cysteine-targeted irreversible mechanism of action on challenging oncology targets such as KRAS.

Citation Format: Gary McCort, Rosalia Arrebola, Loreley Calvet, Baptiste Ronan, Fabrice Vergne, Francis Duffieux, Alexey Rak, Isabelle Meaux, David Papin, Florence Fassy, Cecile Delorme, Magali Matthieu, Jean-Paul Nicolas, Christophe Marcireau, Valerie Steier, Pierre-Yves Abecassis, Valerie Czepczor, Heather A. Thomson, Christopher D. Hupp, J.P. Guilinger, Ying Zhang, Anthony D. Keefe, John W. Cuozzo, Julie Liu, Laurent Debussche. Discovery of novel potent allele-selective KRAS-G12C covalent inhibitors stemming from DNA-encoded library [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3070.
Abstract 3075: Antitumor activity of M8891, a potent and reversible inhibitor of methionine aminopeptidase 2
Authors: Friese-Hamim Manja , Bogatyrova Olga , Ortiz Maria J. , Wienke Dirk , Heinrich Timo , Rohdich Felix , Duecker Klaus , Schultes Christoph , Huck Bayard , Zenke Frank T. , Blaukat Andree
Published: August 2019

N-terminal cleavage of methionine by methionine aminopeptidases is a crucial step in the maturation of proteins during protein biosynthesis. MetAP2, one of the two methionine aminopeptidases expressed in mammalian cells, has been identified as the target of the highly potent and irreversible inhibitor fumagillin to which antiangiogenic and antitumoral properties have been ascribed. This and other findings support the rationale to develop MetAP2 inhibitors for cancer therapy. The fumagillin derivative TNP-470 has been evaluated in several clinical trials, but development was discontinued following demonstration of unfavorable pharmacokinetics and side effects likely attributed to the reactivity of the compound. We have developed M8891, an orally bioavailable, potent, and reversible inhibitor of MetAP2. M8891 inhibited growth of primary endothelial cells as well as patient-derived tumor cells and demonstrated antiangiogenic and antitumoral activity in mouse models. Accumulation of an unprocessed MetAP2 substrate, methionylated elongation factor 1 α, Met-EF1a, was observed upon treatment with M8891 in vitro as well as in vivo confirming that MetAP2 can be effectively inhibited with this compound. In combination with sunitinib, M8891 demonstrated strong and durable antitumor activity in a cohort of patient-derived renal cancer xenografts at well-tolerated exposure levels. Predictive biomarker hypotheses generated from CRISPR sensitivity/resistance screens as well as analyses of molecular profiling data from PDX tumors are currently being evaluated in further nonclinical studies. A dose-escalation phase 1 study in patients with advanced solid tumors is currently ongoing.

Citation Format: Manja Friese-Hamim, Olga Bogatyrova, Maria J. Ortiz, Dirk Wienke, Timo Heinrich, Felix Rohdich, Klaus Duecker, Christoph Schultes, Bayard Huck, Frank T. Zenke, Andree Blaukat. Antitumor activity of M8891, a potent and reversible inhibitor of methionine aminopeptidase 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3075.
Abstract 3085: A novel salicylanilide derivative inhibits castration-resistant prostate cancer via endoplasmic reticulum stress-triggered PERK autophagic signaling pathway
Authors: HSIEH Chia-Ling , Hung Hsu-Shan , Chen Kuan-Chou , Saka Teigi , Chiang Chih-Ying , Sung Shian-Ying
Published: August 2019

Background and Purpose: Metastatic castration-resistant prostate cancer (CRPC) is currently incurable. This study is to extend pharmacological value of our synthesized salicylanilide derivative, that has previously testified for its osteoclastogenesis activity, by exploring its additional cytotoxic properties and underlying mechanism in CRPC cells.

Experimental Approach: LCC03, a 5-(2′,4′-Difluorophenyl)-salicylanilide derivatives, was chemically synthesized and examined for cell growth inhibition in a serial of CRPC cell lines. Possible mechanisms involved in the anticancer activity was elucidated based on the changes in pathway-related protein expression and cellular events, together with antagonists for functional validation. The therapeutic efficacy and safety of LCC03 for the treatment of bone metastatic CRPC was evaluated in an experimental animal model.

Key Results: LCC03 dose-dependently suppressed proliferation and retarded cell cycle progression in CRPC cells. The classical autophagy features including autophagsomes formation and LC3-II conversation were dramatically shown in LCC03-treated CRPC cells, and it was associated with the suppressed AKT/mTOR signaling pathways, a major negative regulator of autophagy, Moreover, an expanded morphology of the ER, increased expression of the ER stress markers GRP78 and PERK, and eIF2α phosphorylation were observed. Blockage of autophagy and PERK pathways using small molecule inhibitors or shRNA knockdown reversed LCC03-induced autophagy and cell death, thus indicating that the PERK-eIF2α pathway contributed to the autophagy induced by LCC03. Furthermore, treatment of tumor-bearing mice with intraperitoneal administered LCC03 suppressed the growth of CRPC xenografts in mouse bone without systemic toxicity.

Conclusion and Implications: LCC03 induces cellular responses toward ER stress-induced autophagy via the PERK-eIF2α pathway that impairs proliferation and cell cycle progression and exhibits cytotoxicity against CRPC cells. The dual action of 5-(2′,4′-difluorophenyl)-salicylanilide on both the osteoclasts and the tumor cells strongly indicates that LCC03 is a promising anticancer candidate for preventing and treating metastatic CRPC.

Citation Format: Chia-Ling HSIEH, Hsu-Shan Hung, Kuan-Chou Chen, Teigi Saka, Chih-Ying Chiang, Shian-Ying Sung. A novel salicylanilide derivative inhibits castration-resistant prostate cancer via endoplasmic reticulum stress-triggered PERK autophagic signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3085.
Abstract 3092: Activation of evolutionarily young transposable elements and the host innate immune system are linked to clinical response to 5-azacitidine
Authors: Ohtani Hitoshi , Ørskov Andreas D. , Helbo Alexandra S. , Gillberg Linn , Liu Minmin , Zhou Wanding , Ungerstedt Johanna , Hellstrom-Lindberg Eva , Sun Weili , Liang Gangning , Jones Peter A. , Grønbæk Kirsten
Published: August 2019

The DNA methyltransferase inhibitors 5-azacitidine (AZA) and 5-aza-2-deoxycytidine (DAC) have been approved for the treatment of higher-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). A more comprehensive understanding of the molecular changes in patients treated with AZA is needed to help explain why only about 50% of these patients have clinical responses. We examined gene expression profiles in a total of 150 RNA samples taken before, during and after treatment with AZA, in three cohorts of patients with hematological cancers (40 patients total; 15 non-responders, 25 responders). We show that activation of the innate immune system is linked to clinical response to AZA treatment. We also measured the induced expression of transposable elements (TEs) to determine whether this was a potential trigger for the immune response. Both responders and non-responders showed robust upregulation of TEs however responders showed the statistically significant upregulation of specific classes of evolutionarily young transposable elements (TEs). These include short and long nuclear elements (SINEs and LINEs) and endogenous retroviruses (ERVs). Moreover, the upregulation of type I interferon signaling pathway genes in responders was significantly higher than non-responders, but not cancer testis antigens (CTAs) or tumor suppressor genes with the exception of CDKN2A and CDKN2B. Therefore, we suggest that induction of specific subsets of silenced evolutionarily young TEs may be a key to the success of epigenetic therapy in hematological cancer patients.

Citation Format: Hitoshi Ohtani, Andreas D. Ørskov, Alexandra S. Helbo, Linn Gillberg, Minmin Liu, Wanding Zhou, Johanna Ungerstedt, Eva Hellstrom-Lindberg, Weili Sun, Gangning Liang, Peter A. Jones, Kirsten Grønbæk. Activation of evolutionarily young transposable elements and the host innate immune system are linked to clinical response to 5-azacitidine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3092.
Abstract 3094: Reclassification of pancreatic adenocarcinoma with distinct fibroblast and immune characteristics and therapeutic targets
Authors: Poudel Pawan , Neuzillet Cindy , Kocher Hemant , Sadanandam Anguraj
Published: August 2019

Pancreatic ductal adenocarcinoma (PDA) with overall poor prognosis is characterized by an abundant desmoplastic stroma comprised of extracellular matrix proteins producing cancer-associated fibroblasts (CAFs). PDA treatment is still primarily based on the use of cytotoxic chemotherapies in unselected patients with modest benefit. To define biomarkers of potential treatment prediction, we (Collisson and Sadanandam; PDAssigner) defined three cancer and four intrinsic CAF (pCAFassigner; first classification to our knowledge) subtypes using PDA patient tumors and primary CAF cultures, respectively. While other groups defined up to four cancer subtypes, there exists additional unrevealed heterogeneity at the level of cancer, stromal and immune cell interactions that defy systematic classification of PDA due to small sample sizes.

To circumvent this issue and to better characterize heterogeneity along with cellular phenotypes, we successfully applied signatures from our pCAFassigner and heterocellular subtypes (representing different cell types/phenotypes of colorectal cancer) along with CIBERSORT to clinical PDA (~757) samples. Interestingly, this analysis identified a subset of our published quasi-mesenchymal (QM)-PDA subtype samples with either increased stem/stroma or inflammatory (not immunogenic subtype) heterocellular characteristics. The stem-like subtype showed variable enrichment of intrinsic CAF (pCAFassigner) subtype characteristics with distinct tumor promoting capabilities (as assessed using CAF:cancer co-culture system) and immune cell interactions. Hence, QM-PDA subtype samples with stem-like characteristics were further split into four stroma-enriched sub-subtypes with significant (p<0.05; log-rank test) differences in patient prognosis. In contrast, the other stem-like QM-PDA subtype patients were enriched for adaptive immunity and may benefit from B cell therapy. On the other hand, inflammatory-enriched QM-PDA subtype samples contained increased macrophages and highly invasive CAFs leading to poorest patient prognosis. These inflammatory subtype patients may respond well to immune therapies targeting macrophages. While all PDA samples are considered to have uniformly high stroma, our study demonstrates that the stromal content is highly variable depending on the sub-subtypes leading to potential personalized therapy responses targeting immune and/or stromal compartments in this devastating cancer type.

Note: This abstract was not presented at the meeting.

Citation Format: Pawan Poudel, Cindy Neuzillet, Hemant Kocher, Anguraj Sadanandam. Reclassification of pancreatic adenocarcinoma with distinct fibroblast and immune characteristics and therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3094.
Abstract 31: Organoid derived from human operative sample of NET shows NET characteristics
Authors: Ichikawa Yasushi , Hiroshima Yukihiko , Kobayashi Noritoshi , Masuda Yusaku , Goto Ayumu , Tokuhisa Motohiko , Takeda Yuma , Ishikawa Takashi , Endo Itaru
Published: August 2019

Background: Neuroendocrine tumor is a rare neoplasm, then, it was difficult to examine using in vitro or animal models. Recently, patient-derived tumor organoid (PDTO) is considered as a promising method to analyze natural characteristics of human tumor, because PDTO is cultured in near-natural circumstances compared with cell lines. We established PDTO of neuroendocrine tumor (NET) utilizing operative samples from a pancreatic NET patient. Aim: Aim of this study is to establish organoid derived from an operative sample of pancreatic NET patient and to compare its characteristics with original tumor using immuno-histochemistry. Material and Method: A pancreatic NET tissue derived from operative sample was cut into small pieces and was treated by collagenase. Prepared tissues were 3-dimensionally cultured on the Matrigel in a serum-free medium (Advanced MEM/F12) with 4 growth factors (Respondin, EGF, Rock inhibitor, Noggin), then PDTO was established. To evaluate growth rate of PDTO, Major axis of the organoid was measured on the day 1, 2, 3, and 6. One week after primary culture of the organoid, subculture was performed. Then major axis of the 2nd, 6th and 7th filial organoid was also measured and compared with each filial. To evaluate characteristics of PDTO as neuroendocrine tumor, immunohistochemistry was performed for the 1st, 2nd and 3rd filial PDTO using anti-chromogranin-A antibody (Dako, mouse IgG), anti-synaptophysin antibody (Abcam, rabbit IgG), anti-NCAM antibody (Abcam mouse IgG) and Neuro-specific enolase (Dako, rabbit IgG). Results: Growth rate of the 2nd and 3rd filial on the day 6 did not show significant difference compared with that of the 1st filial. On the other hand, Growth rate of the 2nd and 3rd filial was significantly lower than that of the 1st filial. Expression of the 4 factors in the 1st, 2nd and 3rd filial PDTO was kept as much as the primary tumor. Conclusion: PDTO derived from neuroendocrine tumor showed the same characteristics as the primary tumor. The 6th and 7th filial PDTO might show cellular aging.

Citation Format: Yasushi Ichikawa, Yukihiko Hiroshima, Noritoshi Kobayashi, Yusaku Masuda, Ayumu Goto, Motohiko Tokuhisa, Yuma Takeda, Takashi Ishikawa, Itaru Endo. Organoid derived from human operative sample of NET shows NET characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 31.
Abstract 3103: Intraparenchymal delivery of chemokines and immunomodulators to eliminate pediatric brain tumor cells
Authors: Nealy Eric S. , DeForest Cole A. , Olson James
Published: August 2019

Pediatric brain tumors are among the leading causes of cancer-related death in children. These malignancies tend to occur in locations of the brain where surgery and radiation can permanently impair a patient’s quality of life. Migratory cells from high grade brain tumors can invade nearby, inaccessible areas of the brain where they may grow unchecked and ultimately lead to patient death. This project seeks to tailor the microenvironment around the tumor cavity to promote the recruitment and elimination of remnant brain tumor cells by microglia and macrophages found in the brain. Our data suggests gradients of classical immune cell chemokines, like CCL2, are also potent chemotactic signals for a variety of patient-derived brain tumor types. Monoclonal antibody blockade of CD47, a cell-surface “don’t eat me” ligand often over-expressed on tumor cells, is effective at promoting the elimination of tumor cells in close-proximity to murine macrophages in vitro. We engineered user-programable hydrogel depots capable of month-long molecule release and implanted them into tumor-bearing mouse brains. Hydrogels incorporated with CCL2 and CD47mAb demonstrated statistically significant co-recruitment of tumor and immune cells and evidence of macrophage-mediated tumor cell death compared to PBS-incorporated gels. These results suggest proper stimulation of immune cells within the brain could be an effective means to eliminate pediatric brain tumor cells without causing structural damage to vital nervous tissues. Our data may be the first steps towards clinical trials for children with incompletely resected brain tumors.

Citation Format: Eric S. Nealy, Cole A. DeForest, James Olson. Intraparenchymal delivery of chemokines and immunomodulators to eliminate pediatric brain tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3103.
Abstract 3113: Regulation of TOR complex 1 by the BRAFV600EMutant determines response and development of resistance to MEK inhibition by trametinib in glioma models
Authors: Li Fuyang
Published: August 2019

Pediatric Low-Grade glioma (PLGG) is the most common brain tumor in children. Current treatment protocols, particularly those involving high dose radiation therapy are associated with neurocognitive and neuroendocrine dysfunction. Genomic studies have revealed that PLGG are characterized by activation of the MAPK cascade. Recently, the value of selumetinib, an allosteric inhibitor of MEK1/2 has been demonstrated in PLGG. However, drug resistance will inevitably limit the efficacy. Trametinib is a more potent MEK1/2 inhibitor with better brain penetration than selumetinib. Here we have attempted to identify the mechanism/s of the resistance to trametinib that PLGG developes, and to explore combination treatments that may retard or prevent emergence of trametinib resistance in animal models.

In BT-40 (childhood anaplastic astrocytoma with BRAFV600E mutation) xenografts, trametinib caused complete tumor regressions, followed by tumor regrowth at the end of treatment. Trametinib treatment rapidly induced pSTAT3(Y705), that was blocked by the JAK1/2 inhibitor, ruxolitinib. Agaist BT-40 xenografts, ruxolitinib slightly enhanced the antitumor response to trametinib. The combination of trametinib with rapamycin was more active in each xenograft line than either single agent alone and in both subcutaneous and intracranial BT-40 models. In BT-40 xenografts, resistance to trametinib was consistently induced within 3 or 4 6-week cycles of treatment similar to that for the trametinib + ruxolitinib combination. In contrast, resistance to combined trametinib and rapamycin was not developed. Rapamycin prevented emergence of trametinib resistance, but did not reverse resistance to trametinib, once acquired. Inhibition of MAPK signaling by trametinib was similar in parental and trametinib-resistant BT-40 xenografts, however, trametinib reistant tumor cells failed to undergo apoptosis. Cells freshly isolated from trametinib resistant BT-40 xenografts had a higher apoptotic threshhold, whereas cells isolated from BT-40 xenografts after 3 cycles of trametinib + rapamycin, remained equally sensitive to parental BT-40 cells, as determined by BH3 profiling. This study reveals a potential new therapeutic use of rapamycin, preventing emergence of resistance to trametinib. Potentially, addition of rapamycin to MEK inhibitor therapy children with BRAF-driven low-grade glioma may be of value.

Citation Format: Fuyang Li. Regulation of TOR complex 1 by the BRAFV600EMutant determines response and development of resistance to MEK inhibition by trametinib in glioma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3113.
Abstract 3120: The novel MEK inhibitor binimetinib decreases cell growth and induces apoptosis in AT/RT
Authors: Shahab Shubin , Rubens Jeffrey , Eberhart Charles , Raabe Eric
Published: August 2019

Atypical teratoid/rhabdoid tumors are a class of malignant CNS tumors disproportionately affecting children with limited therapeutic options. Our group has previously demonstrated that the MAP kinase pathway is altered in a large proportion of these tumors and the MEK inhibitor selumetinib decreases cell growth and promotes apoptosis of AT/RT cells. One of the major drawbacks of selumetinib is its poor blood-brain barrier penetration. Binimetinib is a novel MEK inhibitor currently in pediatric phase II clinical trials for low grade glioma that is thought to have improved brain penetration. Here we demonstrate nanomolar levels of binimetinib successfully decreases cell proliferation and induces apoptosis (2-3 fold induction of cleaved Parp) in AT/RT cell lines, suggesting binimetinib could offer a potential avenue for treating these deadly tumors.

Citation Format: Shubin Shahab, Jeffrey Rubens, Charles Eberhart, Eric Raabe. The novel MEK inhibitor binimetinib decreases cell growth and induces apoptosis in AT/RT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3120.
Abstract 3145: Detection of premature aging among adolescent and young adult osteosarcoma and Ewings sarcoma survivors
Authors: Baker Laurence H. , Reinke Denise , Boonstra Philip , Antalis Erin Peregrine
Published: August 2019

BACKGROUND Bone sarcoma survivors are at high risk for multiple chronic diseases at a young age, which can be characterized as premature aging. Bone sarcoma survivors have the highest cumulative incidence of multiple serious chronic conditions according to analysis of the Childhood Cancer Survivor Study 1. Cardiovascular biomarkers can be used to detect CAD, and enable early intervention in asymptomatic patients.

METHODS

Patients are seen annually at the Sarcoma Survivorship Clinic at the University of Michigan and includes high risk patients over the age of 18 who are at least two years free of disease after treatment completion. Clinical data includes: Blood Pressure, BMI, lipid profile, high sensitivity C-Reactive Protein, and imaging.

RESULTS

30% of patients aged 18-39 exhibit elevations in the cardiovascular biomarker hsCRP, in addition to the traditional biologic markers of elevated lipids, hypertension, and BMI at their most recent clinic visit (Table 1). A subset of patients independently evaluated by 2 nuclear cardiologists also show evidence of coronary artery calcifications (CAC), which is considered pathognomonic of CAD. 40% have been diagnosed with 2 or more of the following chronic diseases: dyslipidemia, obesity, renal insufficiency, anxiety and/or depression, pulmonary disease, cardiovascular disease, thyroid dysfunction, hypertension, liver disease, and anemia.

CONCLUSION

The overall cardiac risk profile among high risk bone sarcoma survivors is characteristic of premature aging. Examining the underlying mechanism of premature aging is essential in this population. Proposed investigation includes alteration of immune pathway as effected by diet, the microbiome, metabolomics, and cellular senescence.

REFERENCES:

1. Gibson TM et al: Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970-99: a report from the Childhood Cancer Survivor Study cohort. The Lancet Oncology 2045:1-12, 2018

Characteristics of bone sarcoma survivors, aged 18-39 (n=20)Chronic Disease Diagnosis%1502253+15Cardiovascular biomarkershsCRP ≥ 2.030BMI ≥ 3015Cholesterol ≥ 200 mg/dL12Hypertension ≥130/8015Glucose ≥ 100 mg/dL20CAC>015

Citation Format: Laurence H. Baker, Denise Reinke, Philip Boonstra, Erin Peregrine Antalis. Detection of premature aging among adolescent and young adult osteosarcoma and Ewings sarcoma survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3145.
Abstract 3146: MFG-E8: A novel prognostic marker for gastric cancer
Authors: Ge Sai , Gao Jing , Shen Lin
Published: August 2019

Gastric cancer is one of the leading causes of cancer-related death all over the world. Milk fat globule-epidermal growth factor (EGF)-factor VIII (MFG-E8) was found to be highly unregulated in a variety of cancers, could induce phagocytosis of apoptotic cells and a significant factor in immune systems. However, its prognostic potential has not been evaluated in gastric cancer (GC). In our former proteomic study, MFG-E8 was found significantly overexpressed in gastric cancer tissues comparing with paired non-cancerous gastric tissues. This study aimed to analyze the association between the expression of MFG-E8 in GC tissues and clinical outcomes in GC patients. In this study, 3 independent cohorts (GSE15460, n = 192; TCGA, n = 380 and ACRG, n = 300) were used to assess MFG-E8 as a biomarker, Kaplan-Meier survival analysis showed that its overexpression was associated with poor prognosis of GC with good discriminative ability in 3 independent cohorts (GSE15460, P <0.001; TCGA, P <0.001 and ACRG, P <0.001). Multivariate analysis further confirmed its prognostic significance (GSE15460, P =0.028; TCGA, P <0.001 and ACRG, P =0.012). These results suggest MFG-E8 may become a potential prognostic factor for GC.

Note: This abstract was not presented at the meeting.

Citation Format: Sai Ge, Jing Gao, Lin Shen. MFG-E8: A novel prognostic marker for gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3146.
Abstract 3147: A novel next generation sequencing strategy for detecting microsatellite instability in colorectal and gastric cancer
Authors: Li Wenyun , Pi Fengmei , Liang Xiaoxia , Cao Taiyuan , Lin Yiheng , Zhai Xiaohui , Huang Mengli , Qin Hao , Gao Chan , Cai Shangli , Wu Xianrui , Xiao Jian , Lan Ping
Published: August 2019

Background: Microsatellite instability (MSI) has become a critical predictive and prognostic biomarker in multiple cancers. The mainstream MSI-detecting techniques, immunohistochemistry (IHC) and polymerase chain reaction (PCR), may have trouble profiling an expanded panel if tissue samples are not available in adequate quantity, depriving patients of treatment options, especially for those with advanced disease. Next generation sequencing, in contrast, allows for massively parallel examination of numerous targets in one single test. In this work, we developed a novel NGS-based assay to detect MSI in colorectal and gastric cancer (CRC/GC) and clinically validated its performance in comparison with IHC and PCR.

Methods: Surgical or biopsy specimens collected from 104 CRC and 15 GC patients were examined for MSI status using IHC, PCR and NGS employing a novel algorithm. The concordance rates between the three techniques were assessed using z-test.

Results: Of the 119 patients enrolled, 53.8% had metastases. IHC tests identified deficient MMR protein expression in 40 (33.6%) cases (dMMR), seven of which were microsatellite stable (MSS) using both PCR and NGS. A discrepancy was also observed for one MMR-proficient (pMMR) case where NGS and IHC consistently produced negative results (pMMR/MSS), while PCR reported a MSI-high (MSI-H) status. The NGS method demonstrated 97.1% (33/34) sensitivity and 100% (85/85) specificity compared to PCR,and 82.5% (33/40) sensitivity and 100% (79/79) specificity compared to IHC. The concordance rate was 99.1% between NGS and PCR, and 94.1% between NGS and IHC. Of the 33 dMMR/MSI-H patients, 30.3% harbored germline defects, suggestive of Lynch Syndrome. In addition, in line with previous reports, the dMMR/MSI-H subset showed a significantly higher median tumor mutational burden (TMB) than the pMMR/MSS patients (P=0.0039).

Conclusion: Our NGS-based approach is reliable and robust for MSI status determination in CRC/GC.

Citation Format: Wenyun Li, Fengmei Pi, Xiaoxia Liang, Taiyuan Cao, Yiheng Lin, Xiaohui Zhai, Mengli Huang, Hao Qin, Chan Gao, Shangli Cai, Xianrui Wu, Jian Xiao, Ping Lan. A novel next generation sequencing strategy for detecting microsatellite instability in colorectal and gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3147.
Abstract 3149: Prognostic impact of PD-L1 expression in correlation with neutrophil-to-lymphocyte ratio in squamous cell carcinoma of the lung
Authors: Yoneda Kazue , Kuwata Taiji , Mori Masataka , Kanayama Masatoshi , Hirai Ayako , Tashima Yuko , Imanishi Naoko , Kuroda Koji , Ichiki Yoshinobu , Tanaka Fumihiro
Published: August 2019

Aim: To investigate the prognostic impact of programmed death-ligand 1 (PD-L1) expression on tumor cells in correlation with neutrophil-to-lymphocyte ratio (NLR) in early-stage squamous cell carcinoma of the lung, as PD-L1 is a potent regulator of cancer immunity and NLR is a potential surrogate of immune status.

Patients and methods: Eighty-three patients with completely resected pathologic stage I lung squamous cell carcinoma were retrospectively reviewed. Tumoral PD-L1 expression was evaluated with immunohistochemistry, and its prognostic impact was analyzed in correlation with NLR.

Results: Forty-three patients (51.8%) had tumor with positive PD-L1 expression (percentage of tumor cells expressing PD-L1, ≥1%). There was no significant correlation between PD-L1 expression and NLR. PD-L1-positivity failed to provide a significant prognostic impact (overall survival [OS] rate at 5 years, 70.1% in PD-L1-negative patients versus 53.0% in PD-L1-positive patients; P=0.117). Among NLR-low (<2.2) patients, however, PD-L1-positivity was significantly correlated with a poor prognosis (OS rate at 5 years, 86.0% in PD-L1-negative patients versus 46.1% in PD-L1-positive patients; P=0.020). In contrast, among NLR-high (≥2.2) patients, PD-L1-positivity provided no prognostic impact (P=0.680). When NLR status and tumoral PD-L1 status were combined, “NLR-low and tumoral PD-L1-negative” was a significant and independent factor to predict a favorable recurrence-free survival (hazard ratio, 0.237 [95% confidence interval, 0.083 to 0.674]; P=0.007) and OS (hazard ratio, 0.260 [95% confidence interval, 0.091 to 0.745]; P=0.012).

Conclusions: The prognostic impact of PD-L1 expression on tumor cells was distinct according to NLR. “NLR-low and tumoral PD-L1-negative” patients showed a favorable prognosis.

Citation Format: Kazue Yoneda, Taiji Kuwata, Masataka Mori, Masatoshi Kanayama, Ayako Hirai, Yuko Tashima, Naoko Imanishi, Koji Kuroda, Yoshinobu Ichiki, Fumihiro Tanaka. Prognostic impact of PD-L1 expression in correlation with neutrophil-to-lymphocyte ratio in squamous cell carcinoma of the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3149.
Abstract 315: Identification of distinct and targetable mechanisms of acquired resistance to CDK4/6 inhibitors
Authors: Parsons Stephen
Published: August 2019

Recently, three CDK4/6 inhibitors were approved by FDA and became effective treatments for ER+ breast cancer patients. However, most if not all patients eventually progress on treatment . To identify mechanisms associated with acquired resistance to CDK4/6 inhibitors, we derived 15 CDK4/6i-resistant variants from human cancer cell lines highly sensitive to CDK4/6 inhibition with abemaciclib or palbociclib. Transcriptome and proteomic profiling of the derivatives revealed four general classes of alteration: decreased RB1, increased CCNE1 or CCNE2, increased ERK phosphorylation, and increased Aurora-A expression. A drug screen was employed to identify drugs or abemaciclib-drug combinations that could suppress growth of the resistant variants. Inhibitors of Aurora-A, Chk1 and the Ras-MAPK pathway were effective for the treatment of the respective classes of resistant derivative. Importantly, Rb loss, Aurora-A amplifications and Ras mutations were all observed as recurrent alterations in biopsies from ER+ breast cancer patients after progression on CDK4/6 inhibitors (1,2). Together these data demonstrate that cancer cells can escape from suppression by CDK4/6 drugs via multiple mechanisms and suggest clinically available therapeutic strategies to treat different classes of resistance.

1. S Wander et al, AACR, 2018

2. R Condorelli et al, Annals of Oncology, vol 29, issue 3, 640-645, 2017

Citation Format: Stephen Parsons. Identification of distinct and targetable mechanisms of acquired resistance to CDK4/6 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 315.
Abstract 3150: Impact of interleukin-1 alpha and EGFR expression on recurrence and survival outcomes in head and neck squamous cell carcinomas
Authors: Simons Andrean L. , Rajan Anand , Gibson-Corley Katherine , Ofori-Amanfo Georgina , Eyck Patrick Ten , Espinosa-Cotton Madelyn , Schmitz Sandra , Coppock Joseph , Sperry Steven
Published: August 2019

Interleukin-1 alpha (IL-1α) is a pleiotropic cytokine involved in inflammation and immune response and is upregulated in many solid tumors including head and neck squamous cell carcinomas (HNSCCs). Although IL-1α expression is generally associated with poor prognosis, the implications of the subcellular localization of IL-1α expression in patient outcomes are poorly understood. This study is aimed at investigating the clinical relevance of immunohistochemical IL-1α expression in HNSCCs. Tissue microarrays (TMAs) containing human papillomavirus (HPV)-positive and HPV-negative HNSCCs were analyzed for IL-1α and epidermal growth factor receptor (EGFR) expression by immunohistochemistry. Nuclear and cytoplasmic IL-1α and EGFR expression scores were correlated with clinicopathological parameters and patient outcomes. IL-1α expression was observed in the nuclear and/or cytoplasm compartments in 98% of evaluable tumors and 78% of tumors expressed IL-1α in both compartments. A higher percentage of tumors with combined high nuclear and moderate cytoplasmic IL-1α expression were observed in HPV-negative tumors compared to HPV-positive tumors. In HPV-negative tumors a combined EGFR-negative and high nuclear IL-1α expression profile was associated with a low risk of tumor recurrence and favorable overall survival compared to all other EGFR/IL-1α expression profiles. Lastly, a higher frequency of tumors with combined high nuclear and moderate cytoplasmic IL-1α expression was observed in cetuximab monotherapy responders compared to non-responders. Altogether, IL-1α in combination with EGFR expression may be a strong indicator of risk of recurrence in HPV-negative HNSCCs and warrants further study as a tissue biomarker for predicting HNSCC patient outcomes.

Citation Format: Andrean L. Simons, Anand Rajan, Katherine Gibson-Corley, Georgina Ofori-Amanfo, Patrick Ten Eyck, Madelyn Espinosa-Cotton, Sandra Schmitz, Joseph Coppock, Steven Sperry. Impact of interleukin-1 alpha and EGFR expression on recurrence and survival outcomes in head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3150.
Abstract 3152: A tumor suppressor-regulated cell cycle derived gene signature is prognostic of recurrence risk in prostate cancer
Authors: Corbin Joshua M. , Georgescu Constantin , Thibivilliers Sandra , Webb Zachary , Zhao Yan , Koster Jan , Fung Kar-Ming , Asch Adam , Wren Jonathan , Ruiz-Echevarria Maria
Published: August 2019

Prostate cancer (PCa) is a complex heterogeneous disease, with the majority of cases remaining indolent and 10% of cases progressing to lethality. While some of this clinical heterogeneity can be explained by traditional clinicopathological factors, molecular profiling studies signal an extraordinary genomic variability, which may lead to diverse clinical outcomes. The identification of molecular subclasses of PCa has the potential to guide the prediction of clinical outcomes, the discovery and design of innovative prognostic biomarkers, and the development of novel therapeutics. To this end, we investigated genes associated with TMEFF2, an androgen-regulated tumor suppressor gene with exceptionally heterogeneous expression in PCa. Low levels of TMEFF2 mRNA significantly (p<0.0001) correlate with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. Using RNA interference, we identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression stratified radical prostatectomy (RP) patients on the risk of recurrence, served as an independent indicator of poor prognosis, and improved the prognostic value of standard clinicopathological markers in four geographically different patient cohorts (n= 834 samples). The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p=0.00017). This study provides evidence that the TMCC11 gene signature is a robust prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, like TMEFF2, as guides to discover prognostic indicators, and suggests the possibility that low TMEFF2 expression marks a distinct subclass of PCa.

Citation Format: Joshua M. Corbin, Constantin Georgescu, Sandra Thibivilliers, Zachary Webb, Yan Zhao, Jan Koster, Kar-Ming Fung, Adam Asch, Jonathan Wren, Maria Ruiz-Echevarria. A tumor suppressor-regulated cell cycle derived gene signature is prognostic of recurrence risk in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3152.
Abstract 3158: Prediction of overall survival in urothelial cancer patients using tumor sizes and baseline risk factors: longitudinal modeling approach for durvalumab and durvalumab + tremelimumab
Authors: Tang Mei , Jiang Yu , Si Han , Zheng Yanan , Gao Chen , Gao Guozhi , Angra Natasha , Abdullah Shaad , Higgs Brandon , Roskos Lorin , Narwal Rajesh
Published: August 2019

Background: Durvalumab [D] is a human mAb that binds to PD-L1 and blocks its interaction with PD-1 and CD80. Tremelimumab [T] blocks the inhibitory effects of CTLA-4, and therefore enhances T-cell activation. The objectives of this analysis were to develop a model linking overall survival (OS) to baseline risk factors and changes in tumor size during treatment to identify key factors impacting response to D or D +T.

Methods: The analysis dataset included UC patients from two clinical trials: Study 1108 (D 10 mg/kg Q2W; n=201) and Study 10 (D 20 mg/kg Q4W + T 1 mg/kg Q4W for 4 doses, followed by D 20 mg/kg Q4W alone; n=168). Longitudinal tumor size data were analyzed using a nonlinear mixed effect model with key parameters describing tumor growth, tumor killing, and delay in immune response. Subsequently, a parametric survival model was developed to link baseline risk factors and predicted percent change in tumor size at week 8 to OS.

Results: Tumor kinetic model adequately described the longitudinal tumor size data from UC patients. Baseline tumor size (p<0.01) and PD-L1 status (p<0.01) were identified as significant covariates for tumor killing rate. The most influential factor associated with faster tumor growth was liver metastasis (p<0.01), while higher hemoglobin levels (p<0.01) were associated with decreased tumor growth rate. Based on parametric survival modeling, liver metastasis (~34% decrease in OS, p<0.0001), albumin (~ 1-fold increase in OS per 1g/dL increase, p<0.0001), and percent change in tumor size at week 8 (~52% increase in OS with 30% tumor shrinkage at week 8, p<0.0001) were found to be significant and clinically relevant predictors of OS.

Conclusions: The parametric survival model coupled with tumor kinetic model adequately described clinical outcomes in UC patients treated with D or D+T and enabled identification of key factors potentially impacting response to immune therapy in UC. This approach can be a useful tool for guiding patient selection/enrichment strategies and optimizing trial designs for immuno-oncology (IO) therapies. Further validation and prospective evaluation of this model may be conducted in other IO trials.

Citation Format: Mei Tang, Yu Jiang, Han Si, Yanan Zheng, Chen Gao, Guozhi Gao, Natasha Angra, Shaad Abdullah, Brandon Higgs, Lorin Roskos, Rajesh Narwal. Prediction of overall survival in urothelial cancer patients using tumor sizes and baseline risk factors: longitudinal modeling approach for durvalumab and durvalumab + tremelimumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3158.
Abstract 316: Parallel activation of MEK as a mechanism of resistance to ALK inhibitor therapy
Authors: Huang Vincent , Yan Yingjun , Qiao Huan , Zhang Yunkai , Lovly Christine M.
Published: August 2019

Chromosomal rearrangements of ALK can result in a fusion protein that serves as an oncogenic driver in non-small cell lung cancer (NSCLC). Although patients with ALK-positive (ALK+) lung cancer have significant response rates when treated with tyrosine kinase inhibitors (TKIs), resistance against ALK targeted therapy consistently develops. Here, we modeled acquired resistance to ALK TKI therapy using 5 different FDA-approved ALK TKIs, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib, using two distinct ALK+ lung cancer cell lines, H3122 and STE-1 (10 resistant cell lines total). Both of these cell lines harbor an EML4-ALK E13;A20 fusion and were derived from patients prior to ALK directed therapy. An ALK kinase domain mutation (F1174L) was detected in the H3122 ceritinib resistant cells, but none of the other resistant cell lines harbored mutations in the ALK kinase domain known to confer TKI resistance. For each of the cell lines tested, we found that ALK TKI treatment in TKI-resistant cells failed to inhibit MAP kinase pathway activity. We hypothesized that inhibition of the MAP kinase pathway, via MEK inhibition, could restore drug sensitivity. The allosteric MEK inhibitors, trametinib and binimetinib, did not effectively reduce cell viability as single agents. However, ALK TKI co-treatment with a MEK inhibitor resensitized these cells by reducing cell viability in a synergistic manner across all ALK TKI-resistant cell lines tested. Whole transcriptomic analysis of ALK TKI-resistant cell lines also revealed an upregulation in EGFR and HER2 mRNA levels. These results provide rationale for combined ALK+MEK inhibitor therapy in patients who have relapsed on first line ALK TKI therapy.

Citation Format: Vincent Huang, Yingjun Yan, Huan Qiao, Yunkai Zhang, Christine M. Lovly. Parallel activation of MEK as a mechanism of resistance to ALK inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 316.