In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4 months (range, 2.4-23.0, 95% confidence interval: 2.6-not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery; deep responses were enriched at higher PRAME expression; and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203 showed promising anti-tumor activity in multiple solid tumors, including refractory melanoma. ClinicalTrials.gov identifier: NCT03686124 .

Rationale of the trial Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors.Trial design The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of 16 patients. IMA202 consists of autologous genetically modified cytotoxic CD8+ T cells expressing a T cell receptor (TCR), which is specific for a nine amino acid peptide derived from MAGEA1. Eligible patients underwent leukapheresis, T cells were isolated, transduced with lentiviral vector carrying MAGEA1-specific TCR and following lymphodepletion (fludarabine/cyclophosphamide), infused with a median of 1.4×109 specific T cells (range, 0.086×109–2.57×109) followed by interleukin 2.Safety of IMA202 No DLT was observed. The most common grade 3–4 adverse events were cytopenias, that is, neutropenia (81.3%), lymphopenia (75.0%), anemia (50.0%), thrombocytopenia (50.0%) and leukopenia (25.0%). 13 patients experienced cytokine release syndrome, including one grade 3 event. Immune effector cell-associated neurotoxicity syndrome was observed in two patients and was grade 1 in both.Efficacy of IMA202 Of the 16 patients dosed, 11 (68.8%) patients had stable disease (SD) as their best overall response (Response Evaluation Criteria in Solid Tumors V.1.1). Five patients had initial tumor shrinkage in target lesions and one patient with SD experienced continued shrinkage in target lesions for 3 months in total but had to be classified as progressive disease due to progressive non-target lesions. IMA202 T cells were persistent in peripheral blood for several weeks to months and were also detectable in tumor tissue. Peak persistence was higher in patients who received higher doses.Conclusion In conclusion, IMA202 had a manageable safety profile, and it was associated with biological and potential clinical activity of MAGEA1-targeting genetically engineered TCR-T cells in a poor prognosis, multi-indication solid tumor cohort.Trial registration numbers NCT04639245, NCT05430555.

Supplementary Table from Inhibition of Karyopherin β1-Mediated Nuclear Import Disrupts Oncogenic Lineage-Defining Transcription Factor Activity in Small Cell Lung Cancer

Abstract Genomic studies support the classification of small cell lung cancer (SCLC) into subtypes based on the expression of lineage-defining transcription factors ASCL1 and NEUROD1, which together are expressed in ∼86% of SCLC. ASCL1 and NEUROD1 activate SCLC oncogene expression, drive distinct transcriptional programs, and maintain the in vitro growth and oncogenic properties of ASCL1 or NEUROD1-expressing SCLC. ASCL1 is also required for tumor formation in SCLC mouse models. A strategy to inhibit the activity of these oncogenic drivers may therefore provide both a targeted therapy for the predominant SCLC subtypes and a tool to investigate the underlying lineage plasticity of established SCLC tumors. However, there are no known agents that inhibit ASCL1 or NEUROD1 function. In this study, we identify a novel strategy to pharmacologically target ASCL1 and NEUROD1 activity in SCLC by exploiting the nuclear localization required for the function of these transcription factors. Karyopherin β1 (KPNB1) was identified as a nuclear import receptor for both ASCL1 and NEUROD1 in SCLC, and inhibition of KPNB1 led to impaired ASCL1 and NEUROD1 nuclear accumulation and transcriptional activity. Pharmacologic targeting of KPNB1 preferentially disrupted the growth of ASCL1+ and NEUROD1+ SCLC cells in vitro and suppressed ASCL1+ tumor growth in vivo, an effect mediated by a combination of impaired ASCL1 downstream target expression, cell-cycle activity, and proteostasis. These findings broaden the support for targeting nuclear transport as an anticancer therapeutic strategy and have implications for targeting lineage-transcription factors in tumors beyond SCLC. Significance: The identification of KPNB1 as a nuclear import receptor for lineage-defining transcription factors in SCLC reveals a viable therapeutic strategy for cancer treatment.

Lineage-defining transcription factors (LTFs) play key roles in small-cell lung cancer (SCLC) pathophysiology. Delineating the LTF-regulated genes operative in SCLC could provide a road map to identify SCLC dependencies. We integrated chromatin landscape and transcriptome analyses of patient-derived SCLC preclinical models to identify super-enhancers (SEs) and their associated genes in the ASCL1-, NEUROD1-, and POU2F3-high SCLC subtypes. We find SE signatures predict LTF-based classification of SCLC, and the SE-associated genes are enriched with those defined as common essential genes in DepMap. In addition, in ASCL1-high SCLC, we show ASCL1 complexes with NKX2-1 and PROX1 to co-regulate genes functioning in NOTCH signaling, catecholamine biosynthesis, and cell-cycle processes. Depletion of ASCL1 demonstrates it is a key dependency factor in preclinical SCLCmodels and directly regulatesmultiple DepMap-defined essential genes. We provide LTF/SE-based subtype-specific gene sets for SCLC for further therapeutic investigation.

Small cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed "variant" due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings may help guide the design of treatment regimens in SCLC.

ASCL1 is a neuroendocrine lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ∼25% of human SCLC are ASCL1-low and associated with low neuroendocrine fate and high MYC expression. Using genetically engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1+ state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1+ subtype of SCLC. Surprisingly, ASCL1 loss promotes a SOX9+ mesenchymal/neural crest stem-like state and the emergence of osteosarcoma and chondroid tumors, whose propensity is impacted by cell of origin. ASCL1 is critical for expression of key lineage-related transcription factors NKX2-1, FOXA2, and INSM1 and represses genes involved in the Hippo/Wnt/Notch developmental pathways in vivo. Importantly, ASCL1 represses a SOX9/RUNX1/RUNX2 program in vivo and SOX9 expression in human SCLC cells, suggesting a conserved function for ASCL1. Together, in a MYC-driven SCLC model, ASCL1 promotes neuroendocrine fate and represses the emergence of a SOX9+ nonendodermal stem-like fate that resembles neural crest.

Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.

Small-cell neuroendocrine (SCN) cancers are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. This has important consequences in that SCN cancers, once considered rare in many tissue types, may become increasingly common with the emergence of resistance cases. Here, we identified a molecular convergence to an SCN state that is more widespread across various epithelial cancers than previously realized, with these additional cases associated with poor prognosis. More broadly, non-SCN metastases have higher expression of SCN-associated transcription factors than non-SCN primary tumors. Drug sensitivity and gene dependency screens demonstrate that these convergent SCN cancers have shared vulnerabilities. These common vulnerabilities are found across unannotated SCN-like epithelial cases, pediatric small round blue cell tumors, and unexpectedly in hematologic malignancies. The SCN convergent phenotype and common sensitivity profiles with hematologic cancers can guide treatment options beyond the limitations of tissue-specific targeted therapies.

ABSTRACT Lineage-defining transcription factors (LTFs) play key roles in tumor cell growth, making them highly attractive, but currently “undruggable”, small cell lung cancer (SCLC) vulnerabilities. Delineating LTF genomic binding sites and associated chromatin features would provide important insights into SCLC dependencies. Here we map super-enhancers (SEs) across multiple patient-derived SCLC preclinical models, and find SE patterns are sufficient to classify the models into the recently defined, LTF-based, SCLC subtypes. 3D-chromatin conformation analysis identified genes associated with SEs that define subtype-specific tumor signatures with genes functioning in diverse processes. Focusing on ASCL1-high SCLC (SCLC-A), we found ASCL1 physically interacts with NKX2-1 and PROX1. These factors bind overlapping genomic regions, and co-regulate a set of genes, including genes encoding cell surface proteins, SCN3A and KCNB2 enriched in SCLC-A. Genetic depletion of NKX2-1 or PROX1 alone, or in combinations with ASCL1, did not inhibit SCLC growth more than that achieved by depleting ASCL1 alone. We demonstrate the SE signature supports the LTF classification of SCLC, identify NKX2-1 and PROX1 as ASCL1 co-factors, and substantiate the central importance of ASCL1 as a key dependency factor in the majority of SCLC. The LTF and SE gene sets provide a molecular roadmap for future ASCL1 therapeutic targeting studies.

Small-cell lung cancer (SCLC) has been treated in the clinic as a single disease, but our previous work demonstrated that MYC drives a unique molecular and therapeutically relevant subset of SCLC (Mollaoglu et al., Cancer Cell 2017; Chalishazar et al., Clin Can Res 2019). Four major molecular subsets of SCLC have now been identified, and they are associated with high expression of four key developmental transcription factors: ASCL1, NEUROD1, POU2F3, and YAP1 (Rudin et al., Nat Rev Can 2019). ASCL1 is a lineage-specific oncogenic driver of SCLC, highly expressed in a significant fraction of tumors, that is required for the development of SCLC in specific mouse models. However, ∼20% of human SCLC are ASCL1-low and associated with a non-neuroendocrine fate and high MYC expression. The role of ASCL1 in the MYC-driven subset of SCLC is unknown. Using genetically engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc can drive SCLC in multiple cell types of origin and that these tumors initially express ASCL1. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation but, surprisingly, converts tumors to an RUNX2+ osteogenic cell fate. Thus, ASCL1 normally represses the osteogenic fate in MYC-driven SCLC arising from multiple cells of origin. MYC-driven SCLC harbors gene signatures that resemble neural crest and mesenchymal stem cells, which have the cell fate options of becoming neuroendocrine or bone. These data suggest that ASCL1 is critical for neuroendocrine tumor cell fate even when initiated in non-neuroendocrine cells. Together, specific genetic alterations can promote remarkable plasticity or deprogramming of adult lung cells, with ASCL1 repressing the emergence of nonendodermal tumor fates.

ASCL1 is a neuroendocrine-lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ~25% of human SCLC are ASCL1-low and associated with low-neuroendocrine fate and high MYC expression. Using genetically-engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1 + state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1 + subtype of SCLC. Surprisingly, ASCL1 loss converts tumors to a SOX9 + mesenchymal/neural-crest-stem-like state that can differentiate into RUNX2 + bone tumors. ASCL1 represses SOX9 expression, as well as WNT and NOTCH developmental pathways, consistent with human gene expression data. Together, SCLC demonstrates remarkable cell fate plasticity with ASCL1 repressing the emergence of non-endodermal stem-like fates that have the capacity for bone differentiation.

Abstracts Presented at the 11th Annual Meeting of the North American Neuroendocrine Tumor Society, October 4–6, 2018, Seattle, Washingtons Presented at the 11th Annual Meeting of the North American Neuroendocrine Tumor Society, October 4–6, 2018, Seattle, Washington LivingWith Neuroendocrine Tumors: AssessingQuality of Life (QoL) Through a Mobile Application Jared Adams, David Ray, Renee Willmon, Anand Gautam, Sonia Pulgar, Arvind Dasari. Self Care Catalysts, San Francisco, CA; Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ; MDAndersonCancer Center, Houston, TX. Background: The aim was to understand neuroendocrine tumor (NET) patients’ QoL through PROMIS-29, symptom tracking and patient journaling via the Carcinoid Health StorylinesTM mobile application (app). Methods: This 12-week prospective, observational study was conducted among US NET patients recruited through the Carcinoid Cancer Foundation on either lanreotide depot or octreotide LAR via surveys at baseline, week 6, and week 12 with PROMIS-29 and symptom questionnaires at baseline, week 4 and week 8. Patients were asked to monitor symptoms, mood, bowel movement frequency, food, activity and sleep in their app 5 /wk. Demographics and medical history were collected at baseline. Results: Of the 120 NET patients, 78% were female (mean age = 57); 76% were gastroenteropancreatic NETs and 88% with metastases. Lanreotide and octreotide use was 41% and 59% respectively. 82% completed ≥ 1 follow-up survey; the most common symptoms at baseline were fatigue (76.7%), diarrhea (62.5%), abdominal discomfort (64.1%) and trouble sleeping (57.5%). The baseline PROMIS-29 assessment revealed high proportions endorsing clinically significant depression (17.7%), anxiety (24.2%), fatigue (58.8%), dissatisfactionwith social role (i.e. daily routine, 42.2%), difficulty with physical functioning (i.e. run errands, 16%) and insomnia (34.9%). Thus, 26.9% reported their QoL being poor and yet, a high percentage of patientswere hopeful and reported their life as being meaningful (72.3%). Reported symptoms decreased significantly from initial to subsequent surveys (e.g. 59.3% to 33% for diarrhea; P = 0.002). App tracking effectively captured variations in reported symptoms and weekly averages correlated wellwith symptom surveys and PROMIS-29 scores. Conclusion: This study suggests the use of apps for recording daily symptoms inNET patients, with decreased symptom reporting over time perhaps due to reduced recall bias from frequent tracking, or a potential therapeutic effect of journaling. Apps should be developed further to record the experiences and needs of NET patients. Co-Administration of rA1M During Lu-177-octreotate Treatment Does Not Interfere With the Therapeutic Effect Charlotte Andersson, Emman Shubbar, Bo Åkerström, Magnus Gram, Eva Forssell-Aronsson. University of Gothenburg, Gothenburg, Sweden; Lund University, Lund, Sweden; A1M Pharma AB, Lund, Sweden. Background: PRRTwith Lu-177-octreotate has yielded promising results in treatment of patients with metastasized NET, but complete tumor remission is scarce. An approach to achieve better tumor control with increased administered activity is to use radioprotectors that limits the side effects on risk organs. A pharmaceutical candidate of alpha-1-microglobulin (rA1M,RMC-035), a human radical scavenger and antioxidant, with the ability to protect tissues from oxidative stress is a conceivable kidney and hematologic protector during PRRT. This study examines co-infusion of rA1M and Lu-177-octreotate in NET-bearing mice with the aim to investigate if rA1M affects therapeutic response to Lu-177-octreotate administration. Methods: The possible effects of rA1M on the change in tumor size after treatment with Lu-177-octreotate were investigated in mice with human small intestine NET, GOT1. The animals were injected with either Lu-177-octreotate, a combination of Lu-177-octreotate and rA1M or rA1M only. Tumor size was measured and followed over time. Furthermore, the biodistribution of Lu-177 after injection of either Lu-177-octreotate, or Lu-177-octreotate and rA1Mwere studied in mice with human medullary thyroid carcinoma, GOT2. The concentration of Lu-177 was determined in various organs at different time points after injection. Pancreas • Volume 48, Number 3, March 2019 Copyright © 2019 Wolters Kluwer Results: Mice treated with Lu-177-octreotate, or Lu-177-octreotate + rA1M had a strong therapeutic response. The tumor remission and re-growth of the tumors in these two groups were similar. Mice receiving only rA1M showed a continuous increase in mean tumor volume after the injection. Concentration of Lu-177 in mouse tissue at different time points after co-injection of Lu177-octreotate and rA1M were not statistically significant different from mice that receiving single injection of Lu-177-octreotate. Conclusion: Administration of rA1M simultaneously with Lu-177-octreotate does not interfere with the therapeutic effects of Lu-177-octreotate. rA1M is a promising radioprotector, and further studies should be performed in order to investigate protective renal and hematologic effects of rA1M during PRRT. Long-term Oncological Outcomes After Distal Pancreatectomy for Neuroendocrine Neoplasms: A Comparison Between Minimally Invasive and Open Approach Using Propensity Score Valentina Andreasi, Stefano Partelli, Paola Maria Rancoita, Eduardo Perez-Sanchez, Francesca Muffatti, Gianpaolo Balzano, Renato Castoldi, Stefano Crippa, Domenico Tamburrino,Massimo Falconi. San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; 2 Vita-Salute University, Milan, Italy. Background: Pancreatic neuroendocrine neoplasms (PanNEN) represent ideal entities for minimally invasive surgery. Several series described laparoscopic surgery for PanNEN demonstrating the advantage of this approach compared to open technique in terms of complications, length of hospital stay and cosmetic results. However, scarce data are available on long-term oncological outcomes. Aim of this study was to compare short-term postoperative outcomes, pathological findings and long-term oncological results of minimally invasive distal pancreatectomy (MIDP) and open distal pancreatectomy (ODP). Methods: Patients who underwent ODP orMIDP for nonfunctioning PanNEN (NF-PanNEN) were retrospectively analyzed. Complications were graded according to the Clavien-Dindo classification. Inverse probability of treatment weighting using propensity score was used to compare the outcomes of minimally invasive and open approach. Results:Overall, 131 patients with NF-PanNENwere included in the study: 84 underwent OPD, whereas 47 underwent MIDP. Median radiological diameter was 25mm (interquartile range, 18-45). The rate of postoperative complications was significantly lower after MIDP (P < 0.001, estimated grade of postoperative complication 0 vs 2) and postoperative length of stay was significantly shorter after MIDP compared to ODP (P < 0.001, 8 vs 11 days). The number of examined lymph nodes (LN) was significantly higher after ODP in comparison to MIDP (P = 0.006, estimated number of LN 13 vs 10). Estimated median follow-up was 77 months (95% confidence interval, 66-85) and overall 22 patients had a recurrence after a median follow-up of 26 months (range, 1-92). Similar progressionfree survival (PFS) and overall survival (OS) were reported for the two groups (P = 0.695 and P = 0.766, respectively). Conclusion: Although MIDP seems to be associated with a lower number of resected LN, long-term survival is not influenced by the type of surgical approach. MIDP is advantageous in terms of postoperative complications and length of stay but prospective studies are needed to confirm the oncological quality of resection in this group of neoplasms. Incidental Histological Diagnosis of Small Pancreatic Neuroendocrine Tumours: Are We Underestimating Their Incidence? Valentina Andreasi, Stefano Partelli, Fabio Giannone, FrancescaMuffatti, Gianpaolo Balzano, StefanoCrippa, Domenico Tamburrino, RobertoMontorsi, Giuseppe Zamboni, Corrado Rubini, Claudio Doglioni, Massimo Falconi. San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; Sacro Cuore-Don Calabria Hospital, Negar, Italy; Polytechnic University of Marche Region, Ancona, Italy. www.pancreasjournal.com 427 Health, Inc. All rights reserved. TABLE 1. Progression Free Survival Based on DLL3 Expression Abstracts Pancreas • Volume 48, Number 3, March 2019 Background: The annual incidence of pancreatic neuroendocrine tumours (PanNET) has been estimated to be around 0.8/100,000 inhabitants. The aim of this study was to determine the frequency of incidental histological diagnosis of PanNET in pancreatic specimens evaluated for other resected neoplasms. Methods: 1023 histopathological examinations of pancreatic specimens performed by three different pathologists in 3 high-volume centers in Italy were retrospectively reviewed. Preoperative evaluations and surgical procedures were performed directly or under the supervision of a single surgeon. All the cases with a main pathological diagnosis of PanNETwere excluded. Results:An incidental associated diagnosis of PanNETwasmade in 38 specimens (4%). NETwas the most frequent (57%) type of associated neoplasm, followed by intraductal papillary mucinous neoplasm (IPMN) (16%). Among those 38 cases, 29 (76%) had a largest diameter ≤5 mm (microadenoma), whereas the other 9 had a maximum length >5 mm (median diameter = 8 mm; range, 7-15 mm). In 9 incidental PanNET a median Ki-67 value of 1% was measured. Patients with incidental PanNETwere significantly older than those in whom a PanNETwas not found (median age: 69 years versus 65.5 years, P = 0.003). A statistically significant difference was found between the finding of a pancreatic neuroendocrine incidentaloma and the main histological diagnosis (P = 0.03). There was no association between incidental diagnosis of PanNET and gender or

Medullary thyroid carcinoma (MTC) is a slow growing neuroendocrine (NE) tumor for which few treatment options are available. Its incidence is rising and mortality rates have remained unchanged for decades. Increasing the repertoire of available treatments is thus crucial to manage MTC progression. Scarcity of patient samples and of relevant animal models are two challenges that have limited the development of effective non-surgical treatments. Here we use a clinically accurate mouse model of MTC to assess the effects and mode of action of the tyrosine kinase inhibitor (TKI) Vandetanib, one of only two drugs currently available to treat MTC. Effects on tumor progression, histopathology, and tumorigenic signaling were evaluated. Vandetanib blocked MTC growth through an anti-angiogenic mechanism. Furthermore, Vandetanib had an apparent anti-angiogenic effect in a patient MTC sample. Vandetanib displayed minimal anti-proliferative effects in vivo and in human and mouse MTC tumor-derived cells. Based on these results, we evaluated the second-generation TKI, Nintedanib, alone and in combination with the histone deacetylase (HDAC) inhibitor, Romidepsin, as potential alternative treatments to Vandetanib. Nintedanib showed an anti-angiogenic effect while Romidepsin decreased proliferation. Mechanistically, TKIs attenuated RET-, VEGFR2- and PI3K/AKT/FOXO signaling cascades. Nintedanib alone or in combination with Romidepsin, but not Vandetanib, inhibited mTOR signaling suggesting Nintedanib may have broader anti-cancer applicability. These findings validate the MTC mouse model as a clinically relevant platform for preclinical drug testing and reveal the modes of action and limitations of TKI therapies.

Studies in genetically engineered mouse models of neuroendocrine lung cancer suggest that differences in cells of origin underlie subtype variations in this class of cancers. These findings highlight the concept that the same driver mutations introduced into different cells of origin lead to tumors with the same histology but dramatically different metastatic programs and potentially different therapeutic responses. (C) 2018 AACR.