Metastatic Cancer Types Research Articles

CDKN2A Alterations and Response to Immunotherapy in Solid Tumors.

Immune checkpoint inhibitors (ICI) have shown clinical benefit in many types of metastatic cancers with only a few predictive biomarkers identified so far. CDKN2A is commonly altered in human cancers, but prior studies have provided conflicting evidence regarding the association between CDKN2A genomic alterations (GA) and response to ICIs. Herein, we examined the impact of loss-of-function CDKN2A alterations on response and survival in patients treated with ICIs. We studied the association between loss-of-function CDKN2A alterations and the response to ICIs in two independent cohorts of six different cancer types. Seven hundred and eighty-nine patients treated at Dana-Farber Cancer Institute (DFCI; Boston, MA) and 1,250 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY) were included in the final analysis. Patients' tumors were sequenced using Oncopanel or MSK-IMPACT. RNA sequencing data from The Cancer Genome Atlas and IMvigor210 were used to investigate differences in the tumor microenvironment. In the DFCI cohort, CDKN2A GAs were associated with poor response and survival in patients with urothelial carcinoma treated with ICIs, but not those treated with platinum-based therapy. Similarly, CDKN2A GAs were associated with worse outcomes in the MSKCC urothelial carcinoma cohort treated with ICIs. There was no association of CDKN2A status with ICI treatment outcome in five other cancers: esophagogastric, head and neck, non-small cell lung, renal cell carcinoma, and melanoma. Immuno-inflammatory pathways were significantly reduced in expression in CDKN2A-altered tumors. Our data show that CDKN2A GAs were associated with reduced benefit from ICI therapy in urothelial carcinoma as well as changes in the tumor-immune microenvironment.

Evaluating DNA Methylation, Gene Expression, Somatic Mutation, and Their Combinations in Inferring Tumor Tissue-of-Origin

Carcinoma of unknown primary (CUP) is a type of metastatic cancer, the primary tumor site of which cannot be identified. CUP occupies approximately 5% of cancer incidences in the United States with usually unfavorable prognosis, making it a big threat to public health. Traditional methods to identify the tissue-of-origin (TOO) of CUP like immunohistochemistry can only deal with around 20% CUP patients. In recent years, more and more studies suggest that it is promising to solve the problem by integrating machine learning techniques with big biomedical data involving multiple types of biomarkers including epigenetic, genetic, and gene expression profiles, such as DNA methylation. Different biomarkers play different roles in cancer research; for example, genomic mutations in a patient’s tumor could lead to specific anticancer drugs for treatment; DNA methylation and copy number variation could reveal tumor tissue of origin and molecular classification. However, there is no systematic comparison on which biomarker is better at identifying the cancer type and site of origin. In addition, it might also be possible to further improve the inference accuracy by integrating multiple types of biomarkers. In this study, we used primary tumor data rather than metastatic tumor data. Although the use of primary tumors may lead to some biases in our classification model, their tumor-of-origins are known. In addition, previous studies have suggested that the CUP prediction model built from primary tumors could efficiently predict TOO of metastatic cancers (Lal et al., 2013; Brachtel et al., 2016). We systematically compared the performances of three types of biomarkers including DNA methylation, gene expression profile, and somatic mutation as well as their combinations in inferring the TOO of CUP patients. First, we downloaded the gene expression profile, somatic mutation and DNA methylation data of 7,224 tumor samples across 21 common cancer types from the cancer genome atlas (TCGA) and generated seven different feature matrices through various combinations. Second, we performed feature selection by the Pearson correlation method. The selected features for each matrix were used to build up an XGBoost multi-label classification model to infer cancer TOO, an algorithm proven to be effective in a few previous studies. The performance of each biomarker and combination was compared by the 10-fold cross-validation process. Our results showed that the TOO tracing accuracy using gene expression profile was the highest, followed by DNA methylation, while somatic mutation performed the worst. Meanwhile, we found that simply combining multiple biomarkers does not have much effect in improving prediction accuracy.

Deciphering molecular mechanisms of metastasis: novel insights into targets and therapeutics.

The transition of a primary tumour to metastatic progression is driven by dynamic molecular changes, including genetic and epigenetic alterations. The metastatic cascade involves bidirectional interactions among extracellular and intracellular components leading to disintegration of cellular junctions, cytoskeleton reorganization and epithelial to mesenchymal transition. These events promote metastasis by reprogramming the primary cancer cell's molecular framework, enabling them to cause local invasion, anchorage-independent survival, cell death and immune resistance, extravasation and colonization of distant organs. Metastasis follows a site-specific pattern that is still poorly understood at the molecular level. Although various drugs have been tested clinically across different metastatic cancer types, it has remained difficult to develop efficacious therapeutics due to complex molecular layers involved in metastasis as well as experimental limitations. In this review, a systemic evaluation of the molecular mechanisms of metastasis is outlined and the potential molecular components and their status as therapeutic targets and the associated pre-clinical and clinical agents available or under investigations are discussed. Integrative methods like pan-cancer data analysis, which can provide clinical insights into both targets and treatment decisions and help in the identification of crucial components driving metastasis such as mutational profiles, gene signatures, associated pathways, site specificities and disease-gene phenotypes, are discussed. A multi-level data integration of the metastasis signatures across multiple primary and metastatic cancer types may facilitate the development of precision medicine and openup new opportunities for future therapies.

Predictive impact of C-reactive protein to albumin ratio for recurrent or metastatic head and neck squamous cell carcinoma receiving nivolumab

Although the neutrophil to lymphocyte ratio (NLR) was reported to be a predictive biomarker for clinical outcomes in various types of cancer, including recurrent or metastatic head and neck cancer (R/M HNSCC) treated with nivolumab, the usefulness of the pretreatment C-reactive protein/albumin ratio (CAR) as a prognostic marker remains to be clarified. This study aimed to analyze the clinical usability of the CAR in comparison with that of the NLR. 46 R/M HNSCC patients treated with nivolumab were retrospectively analyzed. The optimal cutoff value for the CAR was calculated using receiver operating characteristic curve analysis. The optimal cutoff value for the CAR was set to 0.30. On multivariate analyses, a high CAR was significantly associated with poor overall survival (adjusted HR, 2.19; 95% CI, 1.42–3.47; p < 0.01) and progression-free survival (adjusted HR, 1.98; 95% CI, 1.38–2.80; p < 0.01). The overall response rate and disease control rate for the high CAR patients were lower than for the low CAR patients. The CAR had significantly higher area under the curve values than the NLR at 2 and 4 months. The pretreatment CAR might be an independent marker for prognosis and efficacy in R/M HNSCC patients treated with nivolumab.

Clinical results after biliary drainage by endoscopic retrograde cholangiopancreatography for analysis of metastatic cancer survival and prognostic factors.

Malignant biliary obstruction secondary to metastatic cancer is associated with poor prognosis. To the best of our knowledge, no previous study has investigated long-term survival and associated prognostic factors after biliary endoscopic retrograde cholangiopancreatography (ERCP) drainage for obstruction jaundice secondary to various types of metastatic cancer. This retrospective study included 60 patients who underwent biliary ERCP drainage for obstructive jaundice secondary to metastatic cancer at two hospitals during the period from November 2012 to December 2019. Multivariate analysis was conducted to identify independent prognostic factors. Biliary drainage was successfully achieved in 55 (91.7%) patients, 37 of whom received subsequent treatment. Overall median survival time was 133days after stent placement. The overall survival (OS) rates after ERCP drainage were significantly better in the post-drainage treatment group than in the post-drainage untreated group (239days vs. 45days, p < 0.001). Good ECOG performance status before drainage, albumin level ≥ 35g/L, successful drainage, absence of ascites, and post-drainage treatment were identified as factors of improved survival in univariate analysis. ECOG performance status and post-drainage treatment were independent predictors of OS in multivariate analysis. We showed that stent placement with ERCP was a safe and effective treatment method for patients with malignant biliary obstruction caused by metastatic cancer and may be preferred over percutaneous transhepatic biliary drainage. Post-drainage treatment and a good ECOG performance status were predictors of better prognosis.

Differential regulation of mitochondrial complex I and oxidative stress based on metastatic potential of colorectal cancer cells.

Mitochondria serve a vital role in cellular homeostasis as they regulate cell proliferation and death pathways, which are attributed to mitochondrial bioenergetics, free radicals and metabolism. Alterations in mitochondrial functions have been reported in various diseases, including cancer. Colorectal cancer (CRC) is one of the most common metastatic cancer types with high mortality rates. Although mitochondrial oxidative stress has been associated with CRC, its specific mechanism and contribution to metastatic progression remain poorly understood. Therefore, the aims of the present study were to investigate the role of mitochondria in CRC cells with low and high metastatic potential and to evaluate the contribution of mitochondrial respiratory chain (RC) complexes in oncogenic signaling pathways. The present results demonstrated that cell lines with low metastatic potential were resistant to mitochondrial complex I (C-I)-mediated oxidative stress, and had C-I inhibition with impaired mitochondrial functions. These adaptations enabled cells to cope with higher oxidative stress. Conversely, cells with high metastatic potential demonstrated functional C-I with improved mitochondrial function due to coordinated upregulation of mitochondrial biogenesis and metabolic reprogramming. Pharmacological inhibition of C-I in high metastatic cells resulted in increased sensitivity to cell death and decreased metastatic signaling. The present findings identified the differential regulation of mitochondrial functions in CRC cells, based on CRC metastatic potential. Specifically, it was suggested that a functional C-I is required for high metastatic features of cancer cells, and the role of C-I could be further examined as a potential target in the development of novel therapies for diagnosing high metastatic cancer types.

FIT: Functional and imaging testing for patients with metastatic cancer.

Selecting study endpoints in prospective cancer cachexia trials remains poorly defined. The aim of this study was to further evaluate associations in changes in weight, body composition, functional outcomes, and patient-reported outcomes (PROs) in patients with metastatic cancer. We completed a 2-year (2016-2018) observational study in patients with metastatic solid cancer and ECOG performance status 0 to 2 while receiving chemotherapy and/or immunotherapy. We completed assessments at study enrollment and 3months from enrollment. We analyzed longitudinal changes in weight and body composition using validated methods. Functional assessments included the 6-Min Walk Test, Timed Up and Go Test, and Short Physical Performance Battery. PROs included the Functional Assessment of Anorexia/Cachexia Therapy and Functional Assessment of Cancer Therapy Fatigue. We analyzed changes in body composition and functional assessment using paired t tests. Additionally, we utilized linear regression models to assess relationships between changes in body composition and function outcomes and PROs, adjusting for age and sex. A total of 57 patients completed baseline assessments, but 19 patients did not complete 3-month assessments (5 died, 1 hospice, 13 withdrew). Of the 38 patients with complete data, the mean age was 61.8years and 47% were female. Metastatic cancer types included 71% gastrointestinal, 13% lung, and 8% gynecologic. Half received chemotherapy, 16% immunotherapy, and 34% a combination. From enrollment to 3months, we did not observe a change in weight or skeletal muscle but did find an increase in total adipose tissue (16.9 ± 52.4cm2, 95% CI -33.79-0.63; p= 0.059; ~ 1.5 pounds). We did not observe any association with changes in weight with any functional outcomes or PROs. However, greater losses in skeletal muscle were associated with greater declines in physical function (6-Min Walk Test [B= 0.04, p= 0.01], Short Physical Performance Battery [B= 2.44, p< 0.01]). Patients with metastatic cancer receiving cancer-directed therapy may not experience a change in body weight. However, we found an association between losses in skeletal muscle and greater declines in physical function. Therefore, when selecting study endpoints, prospective cancer cachexia studies may consider selecting changes in body composition over weight.

Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types.

Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2 Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.

Pan-metastatic cancer analysis of prognostic factors and a prognosis-based metastatic cancer classification system

We aimed to perform a pan-metastatic cancer analysis on survival and prognostic factors and to create a prognosis-based classification system. We selected distant metastasis patients from the Surveillance, Epidemiology, and End Results (SEER) database. The associations between the characteristics of the patients at admission and overall survival were determined. A prognosis-based metastatic cancer classification was established based on the identified prognostic factors. The differences in prognosis among these categories were tested. The survival rate and prognostic factors were not consistent across cancers. Three metastatic cancer categories were generated, each with different prognoses. The prognostic differences among the categories were satisfactorily validated. Different metastatic cancer types had homogeneous and heterogeneous survival rates and prognostic factors. A prognosis-based classification system for synchronous distant metastasis cancer patients at admission was created. This classification system reflects the grade of malignancy in metastatic cancers and may guide the prediction of survival and individualized treatment. Moreover, it may have important implications for the management of synchronous metastatic cancers and aid clinicians in properly allocating medical resources to metastatic patients.

Assessment of drug utilization pattern in patients undergoing chemotherapy for various types of metastatic cancers in a tertiary care government hospital

Background: Cancer is one among main causes of morbidity and mortality in developing and developed countries. The World Cancer Report 2014 of World Health Organization’s (WHO’s) International Agency for Research on Cancer (IARC), states that in 2012 the global incidence of cancer increased to a 14 million new cases, the figure expected to rise to an annual 19.3 million by 2025. The prescription pattern of anticancer drugs has evolved considerably in recent years because of better understanding of underlying pathophysiology of carcinomas as well as introduction of newer drugs. Methods: It was a hospital-based prospective, cross-sectional study conducted in Department of Oncology, GGH, Kakinada for a period of twelve months from February 2017 to January 2018. A total of 100 patients were enrolled using convenience sampling technique. Patient demographics like age, gender, educational level, employment status, marital status, smoking category, alcohol consumption, stage of cancer was collected. Drug utilization pattern was obtained from inpatient case reports, prescriptions and medication charts used during a chemotherapy cycle.Results: Among all anticancer drugs, cisplatin and 5-flurouracil were most commonly prescribed followed by Adriamycin. The most commonly used adjuvant drugs were B-complex, diclofenac, granisetron, ranitidine, dexamethasone. Antibiotic use was found to be very limited.Conclusions: Various anticancer drug prescription patterns are being used for treatment of patient with metastatic cancers. In this study, cisplatin and 5-flurouracil were commonly used. Injudicious antibiotic prescribing was not observed.

When should we order a next generation sequencing test in a patient with cancer?

Technical advances in genome sequencing and the implementation of next-generation sequencing (NGS) in clinical oncology have paved the way for individualizing cancer patient therapy based on molecular profiles. When and how to use NGS testing in the clinic is at present an unsolved issue, although new research results provide evidence favoring this approach in some types of advanced cancer. Clinical research is evolving rapidly, from basket and umbrella trials to adaptative design precision oncology clinical studies, and genomic and molecular data often displace the classical clinical validation procedures of biomarkers. In this context, physicians must be aware of the clinical evidence behind these new biomarkers and NGS tests available, in order to use them in the right moment, and with a critical point of view. This review will present the status of currently available targeted drugs that can be effective based on actionable molecular alterations, and the NGS tests that are currently available, offering a practical guide for the application of Clinical Precision Oncology in the real world routine practice.

Therapeutic effects of ephrin B receptor 2 inhibitors screened by molecular docking on cutaneous squamous cell carcinoma

Background Cutaneous squamous cell carcinoma (CSCC) is the most known form type of metastatic skin cancer. Activation of ephrin B receptor 2 (EphB2) signaling can promote the metastasis, invasion, and angiogenesis of CSCC cells. Therefore, EphB2 may act as a therapeutic target for CSCC. Here, we screened the inhibitors for EphB2 using molecular docking and then evaluated the effects of the identified inhibitors on cancer-related features of CSCC cells. Methods The Schrodinger docking tool was used to predict the three-dimensional structure of EphB2 protein and its ligand binding sites, and EphB2 inhibitors were screened by high-throughput virtual screening combined with molecular docking. The effects of EphB2 inhibitors were analyzed for cell viability, proliferation, apoptosis, migration, invasion, and xenograft tumor growth. Results In vitro experiments, the identified small-molecule inhibitors markedly inhibited the skin cancer cells proliferation, induced apoptosis, altered the cell cycle, and inhibited cell invasion and migration in our study. In a xenograft model, the identified small-molecule inhibitors induced changes in the epithelial mesenchymal transition, which affected the progression of CSCC. Conclusion EphB2 small-molecule inhibitors had anti-CSCC effects, establishing a solid theoretical basis for clinical research.

Abstract B37: Development of a monoclonal antibody targeting xCT/SLC7A11 expressed in metastatic cancer cells

Abstract The cystine-glutamate antiporter xCT (SLC7A11), the light chain of the antiporter system Xc–, regulates cysteine intake and stimulates the conversion of cysteine and subsequent glutathione (GSH) synthesis, which normally protects cells from oxidative and chemical insults. xCT expression is reported to be low in normal cells but elevated in numerous cancer types, including but not limited to colorectal, breast, pancreatic, and non-small cell lung cancer. Cancer cells have adopted xCT as a means of protection from chemotherapeutic agents and to meet their increased biosynthetic and bioenergetic needs. Additionally, high levels of xCT expression have been reported to correlate with poor patient survival. Thus, our published work and the work of others have established xCT as a novel target for the treatment of metastatic cancer. We have utilized our virus-like particle (VLP) technology and knowledge of xCT to create novel therapeutic monoclonal antibodies that will bind and inhibit the function of xCT expressed on metastatic cancer cells. We bioengineered the presentation of the extracellular domain three (ECD3) of the xCT protein on the surface of our VLP platform and immunized mice to identify biologically active anti-xCT antibodies. We identified 15 subclones that were then selected based upon affinity and avidity to the VLP presenting the ECD3 peptide, the ECD3 peptide itself, and the whole xCT protein, via ELISA. Supernatants were also analyzed using immunofluorescence, to determine the ability to bind xCT expressed on HT-29 cells (human colorectal cancer cell line), MDA-BM-231 cells (human breast cancer cell line), and 4T1 spheroids (mouse breast cancer cell line). One potential candidate, mAb M5, demonstrated specific and high-affinity binding to xCT-expressing cancer cells. mAb M5 was further evaluated in an NSG mouse transplantable model (MDA-MB-231 cells), where primary tumor formation and lung metastases formation were measured. NSG mice were injected subQ with MDA-MB-231 cells and subsequently treated with the mAb M5. We observed that intraperitoneal injections of mAb M5 were able to reduce primary tumor formation and the number of lung metastases when compared to control mice. We also demonstrated in vitro that mAb M5 was able to significantly inhibit spheroid adhesion/spreading. Additionally, mAb M5 was shown in vitro to significantly reduce the uptake of FITC-cystine, which is indicative of xCT inhibition. Therefore, mAb M5 represents a potential therapeutic candidate for multiple metastatic cancer types by inhibiting the function of xCT. Citation Format: Ahmad Salameh, Jerri Caldeira, Valeria Rolih, Elisabetta Bolli, Laura Conti, Michael Perrine. Development of a monoclonal antibody targeting xCT/SLC7A11 expressed in metastatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B37.

Effects of oral maintenance chemotherapy and predictive value of circulating EBV DNA in metastatic nasopharyngeal carcinoma.

Background/ObjectivesOral maintenance chemotherapy can effectively prolong overall survival (OS) in many types of metastatic cancer, but its role in metastatic nasopharyngeal carcinoma (mNPC) is unclear. In this study, the efficacy of oral maintenance chemotherapy in mNPC and the effectiveness of circulating tumor EBV‐DNA for screening patients were evaluated.MethodsBetween June 2016 and December 2017, 141 patients with mNPC who received platinum‐based systemic chemotherapy were included (median follow‐up time, 21 months). Patients were classified into two groups according to the administration of oral maintenance chemotherapy. Plasma samples were collected before, during, and after treatment for the measurement of circulating EBV DNA.ResultsThe 2‐year OS was higher for patients who received maintenance chemotherapy than for patients without maintenance chemotherapy (78.9% vs 62.7%, P = .016). Patients with undetectable posttreatment EBV‐DNA after 4‐6 cycles of systemic chemotherapy (n = 73) had a higher 2‐year OS than that of patients with detectable EBV‐DNA (n = 68) (82.16% vs 51.45%, P = .001). For patients with undetectable posttreatment EBV‐DNA, OS was better for those with maintenance chemotherapy than for those without (86.7% vs 73%, P = .027). For patients with detectable posttreatment EBV‐DNA, maintenance chemotherapy did not improve outcomes (49.5% vs 55.4%, P = .824). The most common acute events were hematological toxicity, and all were tolerable and curable.ConclusionsOral maintenance chemotherapy with S1 or capecitabine can improve OS in mNPC. Posttreatment EBV‐DNA was not only an independent prognosis factor for mNPC but also can screen out beneficiaries of maintenance chemotherapy.

Metastatic only primitive neuroectodermal tumor: smoke without fire can be more dangerous

Multiple, diffuse, well circumscribed large pulmonary nodules as an incidental finding is pathognomonic for disseminated cancer. For all cancers, the lung is the second most common site of metastasis after the liver (1,2) and the most common for Ewing Sarcoma family of tumors (ESFT) (3). Disseminated disease at presentation signifies poor prognosis regardless of the cancer origin, however both the treatment regimen and treatment response as well as the ultimate outcome is highly dependent on the type of metastatic cancer, and thus the first step is to obtain tissue diagnosis. While less invasive strategies always appear to be less morbid, they can be non-diagnostic and prolong time to treatment. Definitive surgical biopsies are invasive but conclusive and, despite slightly higher morbidity, end up being more effective.

Eribulin Suppresses New Metastases in Patients With Metastatic Breast Cancer.

This study aimed to investigate the progression type of metastatic breast cancer (MBC) in patients undergoing eribulin chemotherapy. We retrospectively investigated the cases of 66 consecutive patients with MBC who underwent eribulin chemotherapy. A total of 15 patients (22.7%) received eribulin as a 3rd-line or later treatment, and 17 (25.8%) received eribulin as a 1st-line treatment. The overall response was complete response in 0 (0%), partial response in 15 (22.7%), stable disease in 27 (40.9%), and progressive disease in 24 (36.4%) patients. By the time of data cut-off, time to treatment failure (TTF) events had been observed in 60 patients (90.9%), among whom, 15 (25%) had disease progression due to NM, and 45 (75%) had disease progression due to PL. In the regimen before eribulin administration, among 49 patients, 24 (49.0%) had disease progression due to NM. Luminal-type patients and those with triple-negative breast cancer exhibited a similar tendency, i.e., the rate of NM was lower in the patients treated with eribulin. The rate of NM was lower in the patients treated with eribulin in the 1st-line setting than that in patients treated with eribulin as a later treatment. Eribulin has a potential antitumor mechanism to prevent new metastasis. Eribulin may be effective against both the epithelial-mesenchymal transition (EMT) process and new metastasis.

Tanapoxvirus: From discovery towards oncolytic immunovirotherapy.

Insufficiency of standard cancer therapeutic agents and a high degree of toxicity associated with chemotherapy and radiotherapy have created a dearth of therapeutic options for metastatic cancers. Oncolytic viruses (OVs) are an emerging therapeutic option for the treatment of various human cancers. Several OVs, including poxviruses, are currently in preclinical and clinical studies and have shown to be effective in treating metastatic cancer types. Tanapoxvirus (TANV), a member of the Poxviridae family, is being developed as an OV for different human cancers due to its desirable safety and efficacy features. TANV causes a mild self-limiting febrile disease in humans, does not spread human to human, and its large genome makes it a relatively safer OV for use in humans. TANV is relatively well characterized at both molecular and clinical levels. Some of the TANV-encoded proteins that are a part of the virus' immune evasion strategy are also characterized. TANV replicates considerably slower than vaccinia virus. TANV has been shown to replicate in different human cancer cells in vitro and regresses human tumors in a nude mouse model. TANV is currently being developed as a therapeutic option for several human cancers including breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, retinoblastoma, and melanoma. This review provides a comprehensive summary from the discovery to the development of TANV as an OV candidate for a wide array of human cancers.

Study of VE800 and Nivolumab in Patients With Selected Types of Advanced or Metastatic Cancer

Study of VE800 and Nivolumab in Patients With Selected Types of Advanced or Metastatic Cancer

Axon-like protrusions promote small cell lung cancer migration and metastasis.

Metastasis is the main cause of death in cancer patients but remains a poorly understood process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic cancer types. SCLC cells normally express neuroendocrine and neuronal gene programs but accumulating evidence indicates that these cancer cells become relatively more neuronal and less neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The formation of these protrusions is controlled by multiple neuronal factors implicated in axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option of developmental neuronal programs is a novel molecular and cellular mechanism that contributes to the high metastatic ability of SCLC.

Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer.

Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu. Non-ICI-treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non-small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy. TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI-treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors. The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.