CAR-T Therapies in Solid Tumors: Opportunities and Challenges.

PURPOSE OF REVIEW: This review will discuss the challenges facing chimeric antigen receptor (CAR)-T cell application for solid tumors and opportunities to overcome these obstacles. In addition, this review will examine therapies that are in development for pediatric solid tumors. RECENT FINDINGS: The similar success of CAR-T cell treatment for hematological malignancies has not been observed in solid tumors because of the hostile tumor microenvironment and tumor heterogeneity. Most strategies developed to combat these limitations emphasize combinatorial techniques that still require further testing. Preliminary results of multiple clinical trials, including GD2- and HER2-CAR-T cells, are encouraging but must be reproduced and validated on a larger scale. CAR-T cell application in solid tumors remains challenging, and most research is in development. Several clinical trials are ongoing for pediatric solid tumors. Early results are promising but demonstrate the need for CAR-T cell modification to prevent tumor recurrence.

Synthesis and Anti-Melanoma Activity of Acryloyl Pyridinone Analogues.

A major challenge for clinical management of melanoma is the prevention and treatment of metastatic disease. Drug discovery efforts over the last 10 years have resulted in several drugs that improve the prognosis of metastatic melanoma; however, most patients develop early resistance to these treatments. We designed and synthesized, through a concise synthetic strategy, a series of hybrid olefin-pyridinone compounds that consist of structural motifs from tamoxifen and ilicicolin H. These compounds were tested against a human melanoma cell line and patient-derived melanoma cells that had metastasized to the brain. Three compounds 7 b, 7 c, and 7 g demonstrated promising activity (IC50=0.4-4.3 µM). Cell cycle analysis demonstrated that 7 b and 7 c induce cell cycle arrest predominantly in the G1 phase. Both 7 b and 7c significantly inhibited migration of A375 melanoma cells; greater effects were demonstrated by 7 b. Molecular modelling analysis provides insight into a plausible mechanism of action.

Zebrafish Cancer Avatars: A Translational Platform for Analyzing Tumor Heterogeneity and Predicting Patient Outcomes.

The increasing number of available anti-cancer drugs presents a challenge for oncologists, who must choose the most effective treatment for the patient. Precision cancer medicine relies on matching a drug with a tumor's molecular profile to optimize the therapeutic benefit. However, current precision medicine approaches do not fully account for intra-tumoral heterogeneity. Different mutation profiles and cell behaviors within a single heterogeneous tumor can significantly impact therapy response and patient outcomes. Patient-derived avatar models recapitulate a patient's tumor in an animal or dish and provide the means to functionally assess heterogeneity's impact on drug response. Mouse xenograft and organoid avatars are well-established, but the time required to generate these models is not practical for clinical decision-making. Zebrafish are emerging as a time-efficient and cost-effective cancer avatar model. In this review, we highlight recent developments in zebrafish cancer avatar models and discuss the unique features of zebrafish that make them ideal for the interrogation of cancer heterogeneity and as part of precision cancer medicine pipelines.

Basilar decompression via a far lateral transcondylar approach: technical note.

BACKGROUND: Treatments for symptomatic or unstable basilar invagination (BI) include posterior decompression, distraction/fusion, trans-nasal or trans-oral anterior decompression, and combined techniques, with the need for occipitocervical fusion based on the degree of craniocervical instability. Variations of the far lateral transcondylar approach are described in limited case series for BI, but have not been widely applied. METHODS: A single-institution, retrospective review of consecutive patients undergoing a far lateral transcondylar approach for odontoidectomy (± resection of the inferior clivus) followed by occipitocervical fusion over a 6-year period (1/1/2016 to 12/31/2021) is performed. Detailed technical notes are combined with images from cadaveric dissections and patient surgeries to illustrate our technique using a lateral retroauricular incision. RESULTS: Nine patients were identified (3 males, 6 females; mean age 40.2 ± 19.6 years). All patients had congenital or acquired BI causing neurologic deficits. There were no major neurologic or wound-healing complications. 9/9 patients (100%) experienced improvement in preoperative symptoms. CONCLUSIONS: The far lateral transcondylar approach provides a direct corridor for ventral brainstem decompression in patients with symptomatic BI. A comprehensive knowledge of craniovertebral junction anatomy is critical to the safe performance of this surgery, especially when using a lateral retroauricular incision.

Racial and ethnic disparities among children with primary central nervous system tumors in the US.

INTRODUCTION: Primary central nervous system (CNS) tumors are among the most common and lethal types of cancer in children. However, the existence of health disparities in CNS tumors by race or ethnicity remains poorly understood. This systematic review sought to determine whether racial and ethnic disparities in incidence, healthcare access, and survival exist among pediatric patients diagnosed with CNS tumors. METHODS: A search of MEDLINE, Embase, CINAHL, Web of Science, and Scopus was conducted. Inclusion criteria selected for studies published between January 1, 2005 and July 15, 2020 that focused on pediatric populations in the US, evaluated for potential differences based on racial or ethnic backgrounds, and focused on CNS tumors. A standardized study form was used to collect study information, population of interest, research design, and quality of analysis, sample size, participant demographics, pathology evaluated, and incidence or outcomes observed. RESULTS: A total of 30 studies were inlcuded. Studies suggest White children may be more likely to be diagnosed with a CNS tumor and Hispanic children to present with advanced-stage disease and have worse outcomes. The degree of influence derived from socioeconomic factors is unclear. This review was limited by few available studies that included race and ethnicity as a variable, the overlap in databases used, and unclear categorization of race and ethnicity. CONCLUSIONS: This review identified notable and at times contradicting variations in racial/ethnic disparities among children with CNS tumors, suggesting that the extent of these disparities remains largely unknown and prompts further research to improve health equity.

Biobanked Glioblastoma Patient-Derived Organoids as a Precision Medicine Model to Study Inhibition of Invasion.

Glioblastoma (GBM) is highly resistant to treatment and invasion into the surrounding brain is a cancer hallmark that leads to recurrence despite surgical resection. With the emergence of precision medicine, patient-derived 3D systems are considered potentially robust GBM preclinical models. In this study, we screened a library of 22 anti-invasive compounds (i.e., NF-kB, GSK-3-B, COX-2, and tubulin inhibitors) using glioblastoma U-251 MG cell spheroids. We evaluated toxicity and invasion inhibition using a 3D Matrigel invasion assay. We next selected three compounds that inhibited invasion and screened them in patient-derived glioblastoma organoids (GBOs). We developed a platform using available macros for FIJI/ImageJ to quantify invasion from the outer margin of organoids. Our data demonstrated that a high-throughput invasion screening can be done using both an established cell line and patient-derived 3D model systems. Tubulin inhibitor compounds had the best efficacy with U-251 MG cells, however, in ex vivo patient organoids the results were highly variable. Our results indicate that the efficacy of compounds is highly related to patient intra and inter-tumor heterogeneity. These results indicate that such models can be used to evaluate personal oncology therapeutic strategies.

Association of Insurance Status With Treatment and Outcomes in Pediatric Patients With Severe Traumatic Brain Injury.

OBJECTIVE: To determine whether a health insurance disparity exists among pediatric patients with severe traumatic brain injury using the National Trauma Data Bank. DESIGN: Retrospective cohort study. SETTING: National Trauma Data Bank, a dataset containing more than 800 trauma centers in the United States. PATIENTS: Pediatric patients (< 18 yr old) with a severe isolated traumatic brain injury were identified in the National Trauma Database (years 2007-2016). Isolated traumatic brain injury was defined as patients with a head Abbreviated Injury Scale score of 3+ and excluded those with another regional Abbreviated Injury Scale of 3+. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Procedure codes were used to identify four primary treatment approaches combined into two classifications: craniotomy/craniectomy and external ventricular draining/intracranial pressure monitoring. Diagnostic criteria and procedure codes were used to identify condition at admission, including hypotension, Glasgow Coma Scale, mechanism and intent of injury, and Injury Severity Score. Children were propensity score matched using condition at admission and other characteristics to estimate multivariable logistic regression models to assess the associations among insurance status, treatment, and outcomes. Among the 12,449 identified patients, 91.0% (n = 11,326) had insurance and 9.0% (n = 1,123) were uninsured. Uninsured patients had worse condition at admission with higher rates of hypotension and higher Injury Severity Score, when compared with publicly and privately insured patients. After propensity score matching, having insurance was associated with a 32% (p = 0.001) and 54% (p < 0.001) increase in the odds of cranial procedures and monitor placement, respectively. Insurance coverage was associated with 25% lower odds of inpatient mortality (p < 0.001). CONCLUSIONS: Compared with insured pediatric patients with a traumatic brain injury, uninsured patients were in worse condition at admission and received fewer interventional procedures with a greater odds of inpatient mortality. Equalizing outcomes for uninsured children following traumatic brain injury requires a greater understanding of the factors that lead to worse condition at admission and policies to address treatment disparities if causality can be identified.

SMARC-B1 deficient sinonasal carcinoma metastasis to the brain with next generation sequencing data: a case report of perineural invasion progressing to leptomeningeal invasion.

BACKGROUND: SMARCB1-deficient sinonasal carcinoma (SDSC) is an aggressive subtype of head and neck cancers that has a poor prognosis despite multimodal therapy. We present a unique case with next generation sequencing data of a patient who had SDSC with perineural invasion to the trigeminal nerve that progressed to a brain metastasis and eventually leptomeningeal spread. CASE PRESENTATION: A 42 year old female presented with facial pain and had resection of a tumor along the V2 division of the trigeminal nerve on the right. She underwent adjuvant stereotactic radiation. She developed further neurological symptoms and imaging demonstrated the tumor had infiltrated into the cavernous sinus as well as intradurally. She had surgical resection for removal of her brain metastasis and decompression of the cavernous sinus. Following her second surgery, she had adjuvant radiation and chemotherapy. Several months later she had quadriparesis and imaging was consistent with leptomeningeal spread. She underwent palliative radiation and ultimately transitioned quickly to comfort care and expired. Overall survival from time of diagnosis was 13 months. Next generation sequencing was carried out on her primary tumor and brain metastasis. The brain metastatic tissue had an increased tumor mutational burden in comparison to the primary. CONCLUSIONS: This is the first report of SDSC with perineural invasion progressing to leptomeningeal carcinomatosis. Continued next generation sequencing of the primary and metastatic tissue by clinicians is encouraged toprovide further insights into metastatic progression of rare solid tumors.

Effects of thioTEPA chemotherapy on cognition and motor coordination.

Cancer survivorship has increased greatly as therapies have become more advanced and effective. Thus, we must now focus on improving the quality of life of patients after treatment. After chemotherapy, many patients experience chemotherapy-induced cognitive decline, indicating a need to investigate pathologies associated with this condition. In this study, we addressed cognitive impairment after thioTEPA treatment by assessing behavior and assaying cytokine production and the structure of dendrites in the hippocampus. Male mice were given three intraperitoneal injections of thioTEPA. Five weeks later, the mice underwent behavior testing, and brains were collected for Golgi staining and cytokine analysis. Behavior tests included y-maze and Morris water maze and licking behavioral task. Cytokines measured include: IL-1α, IL-1ß, IL-2, IL-3, IL-4, IL-5, IL-10, IL-12p70, MCP-1, TNF-α, GMCSF, and RANTES. We observed decreased memory retention in behavioral tasks. Also, dendritic arborization and length were decreased after chemotherapy treatment. Finally, thioTEPA decreased cytokine production in animals treated with chemotherapy, compared to saline-treated controls. Here, we used a mouse model to correlate the decreases in dendritic complexity and inflammatory cytokine production with cognitive impairment after chemotherapy.

Long-Term Changes in Cognition and Physiology after Low-Dose 16O Irradiation.

Astronauts traveling to Mars will be exposed to high levels of ionizing radiation upon leaving low-Earth orbit. During prolonged space travel, astronauts are exposed to galactic cosmic rays (GCRs) composed of protons; oxygen molecules; and high energy, high mass charged particles. Notably, oxygen molecules can travel through the shielding of spacecraft, potentially impacting 25% of the hippocampus. The aim of the current study was to assess whether 16O-particle radiation induced a behavioral deficit and histological changes in mice. Mice were sent to the National Aeronautics and Space Administration (NASA) Space Radiation Laboratory at Brookhaven National Laboratory and exposed to particulate 16O radiation at doses of 0 and 0.05 Gy. Nine months after irradiation, the mice were tested for novel object recognition and in the Y-maze, after which the animals were sacrificed. The brains were then dissected along the midsagittal plane for Golgi staining. Exposure to 0.05 Gy significantly impaired novel object recognition. However, short term memory and exploratory activity in the Y-maze were not affected. Micromorphometric analysis revealed significant decreases in mushroom spine density in the dentate gyrus and cornu Ammonis-1 and -3 of the hippocampus. Sholl analysis revealed a significant decrease in dendritic complexity in the dentate gyrus. The present data provide evidence that space radiation has deleterious effects on mature neurons associated with hippocampal learning and memory.

Novel placement of cortical bone trajectory screws in previously instrumented pedicles for adjacent-segment lumbar disease using CT image-guided navigation.

OBJECT: Symptomatic adjacent-segment lumbar disease (ASLD) after lumbar fusion often requires subsequent surgical intervention. The authors report utilizing cortical bone trajectory (CBT) pedicle screw fixation with intraoperative CT (O-arm) image-guided navigation to stabilize spinal levels in patients with symptomatic ASLD. This unique technique results in the placement of 2 screws in the same pedicle (1 traditional pedicle trajectory and 1 CBT) and obviates the need to remove preexisting instrumentation. METHODS: The records of 5 consecutive patients who underwent lumbar spinal fusion with CBT and posterior interbody grafting for ASLD were retrospectively reviewed. All patients underwent screw trajectory planning with the O-arm in conjunction with the StealthStation navigation system. Basic demographics, operative details, and radiographic and clinical outcomes were obtained. RESULTS: The average patient age was 69.4 years (range 58-82 years). Four of the 5 surgeries were performed with the Minimal Access Spinal Technologies (MAST) Midline Lumbar Fusion (MIDLF) system. The average operative duration was 218 minutes (range 175-315 minutes). In the entire cohort, 5.5-mm cortical screws were placed in previously instrumented pedicles. The average hospital stay was 2.8 days (range 2-3 days) and there were no surgical complications. All patients had more than 6 months of radiographic and clinical follow-up (range 10-15 months). At last follow-up, all patients reported improved symptoms from their preoperative state. Radiographic follow-up showed Lenke fusion grades of A or B. CONCLUSIONS: The authors present a novel fusion technique that uses CBT pedicle screw fixation in a previously instrumented pedicle with intraoperative O-arm guided navigation. This method obviates the need for hardware removal. This cohort of patients experienced good clinical results. Computed tomography navigation was critical for accurate CBT screw placement at levels where previous traditional pedicle screws were already placed for symptomatic ASLD.

SMARCA4-deficient central nervous system metastases: A case series and systematic review.

SMARCA4 alterations can be encountered in a variety of human neoplasms, and metastases to the central nervous system (CNS) are rare, offering a challenge to neuropathologists despite not representing a distinct diagnostic entity. To better understand the clinical and histologic presentation of such neoplasms, we report an observational case series and systematic review of 178 unique articles that yielded 15 published cases and 7 cases from institutional files. In the systematic review, the median age was 58 years, the male-to-female ratio was 2:1, and the most common diagnosis was lung adenocarcinoma; all CNS metastases were discovered within 1 year of presentation. In the case series, the median age was 58 years, the male-to-female ratio was 6:1, and all known metastases originated from the lung. Most patients had a smoking history and died of disease. GATA-3 positivity was seen in most case series examples. Concurrent TP53 mutations (83.3%) and a high tumor mutation rate (60%) were common. To our knowledge, this is the only case series and systematic review in the English literature aimed at assessing SMARCA4-altered metastases in the CNS and vertebral column. We highlight the challenges of neuropathologic evaluation of such tumors and provide observational evidence of early metastases, histologic appearances, and immunohistochemical findings, including previously unreported GATA-3 positivity.

Functional precision medicine assay for recurrent meningioma: a proof of principle. Illustrative case.

BACKGROUND: Meningiomas are the most prevalent primary central nervous system tumors. Although low-grade meningiomas are considered benign tumors, a subset of these can behave aggressively, showing progression and recurrence. In such cases, functional assays could influence treatment decisions and improve patient outcomes. OBSERVATIONS: A 78-year-old female presented with a long-standing history of a supratentorial meningioma that was initially resected and treated with Gamma Knife radiosurgery. Surveillance revealed progression. She began systemic therapy with everolimus and octreotide but was lost to follow-up and did not continue the treatment. She returned because of a rapid decline in her neurological status. Biopsy with advanced molecular characterization by next-generation sequencing revealed NF2 and CREBBP mutations, and a commercial functional assay was done. This assay successfully isolated cancer stem cells (CSCs) from biopsy cores and identified potential drugs based on cellular sensitivity profiles. This is the first reported case in which a commercial functional drug screen was used for a meningioma. LESSONS: In cases in which meningiomas exhibit specific genetic alterations and characteristics of aggressiveness, functional assays can be a useful tool for isolating CSCs. The authors report success in obtaining drug-screen profiling for a World Health Organization grade 1 meningioma. Multimodal approaches utilizing multi-omics analyses with functional assays can improve patient outcomes. https://thejns.org/doi/10.3171/CASE24242.

A rare case of atypical intradural extramedullary glioblastoma diagnosed utilizing next-generation sequencing and methylation profiling: illustrative case.

BACKGROUND: Primary spinal cord tumors, especially primary spinal cord glioblastoma multiforme (PSC-GBM), are exceptionally rare, accounting for less than 1.5% of all spinal tumors. Their infrequency and aggressive yet atypical presentation make diagnosis challenging. In uncertain cases, a surgical approach for tissue diagnosis is often optimal. OBSERVATIONS: A 76-year-old male presented with a rapidly progressing clinical history marked by worsening extremity weakness, urinary retention, and periodic fecal incontinence alongside diffuse changes on neuraxis imaging. The patient, in whom subacute polyneuropathy was initially diagnosed, received multiple rounds of steroids and intravenous immunoglobulin without clinical improvement. Histopathological review of the biopsy tissue yielded an initial diagnosis of spindle cell neoplasm. Next-generation sequencing (NGS) is done routinely on all neuropathology specimens at the authors' institution, and methylation profiling is pursued in difficult cases. Ultimately, NGS and methylation profiling results were essential to an integrated final diagnosis of GBM. LESSONS: PSC-GBM is a rare but highly aggressive occurrence of this tumor. Prolonged back pain, rapid neurological decline, and imaging changes warrant the consideration of lesional biopsy for precise disease characterization. In inconclusive cases, NGS has proved invaluable for clinical clarification and diagnosis, underscoring its importance for integrated diagnoses in guiding appropriate treatment strategies.

Long-read sequencing for brain tumors.

Brain tumors and genomics have a long-standing history given that glioblastoma was the first cancer studied by the cancer genome atlas. The numerous and continuous advances through the decades in sequencing technologies have aided in the advanced molecular characterization of brain tumors for diagnosis, prognosis, and treatment. Since the implementation of molecular biomarkers by the WHO CNS in 2016, the genomics of brain tumors has been integrated into diagnostic criteria. Long-read sequencing, also known as third generation sequencing, is an emerging technique that allows for the sequencing of longer DNA segments leading to improved detection of structural variants and epigenetics. These capabilities are opening a way for better characterization of brain tumors. Here, we present a comprehensive summary of the state of the art of third-generation sequencing in the application for brain tumor diagnosis, prognosis, and treatment. We discuss the advantages and potential new implementations of long-read sequencing into clinical paradigms for neuro-oncology patients.

Immune checkpoint inhibitors as subsequent treatment in older adults with non-small cell lung cancer and synchronous brain metastases.

Background: Immune checkpoint inhibitors (ICIs) have become the mainstay treatment for non-small cell lung cancer (NSCLC). However, there is a lack of studies assessing ICIs as subsequent treatment in older adults with NSCLC and brain metastasis (BM). This retrospective cohort study compared the real-world survival of older patients with NSCLC and BM at diagnosis [synchronous BM (SBM)] previously treated with chemotherapy receiving ICI versus chemotherapy as subsequent treatment. Methods: Patients with NSCLC and SBM ≥65 years previously treated with chemotherapy were identified using the SEER-Medicare database (2010-2019). Patients receiving new chemotherapy and/or Food and Drug Administration (FDA)-approved ICIs as second/third-line treatment were included, excluding those ever-receiving targeted therapies. Each ICI patient was matched to one chemotherapy patient by time to subsequent treatment (within ±30 days) from diagnosis. Overall survival (OS) time was measured from the start of subsequent treatment to death, censored at disenrollment from Medicare Part A/B, enrollment in Part C, or end of study (December 31, 2019), whichever came first. OS curves were estimated and compared using the Kaplan-Meier (KM) method and log-rank test. Hazard ratio (HR) was estimated using a multivariable-adjusted Cox proportional hazards model. Results: Matched cohorts included 546 patients [273 in each group; median age 71 (range, 65-87) years]. ICI patients were older, more likely non-Hispanic, with squamous cell carcinoma, and liver metastasis compared to chemotherapy. KM estimated better survival in ICI than chemotherapy {median survival: 209 days [95% confidence interval (CI): 160-275] vs. 155 days (95% CI: 135-187); log-rank P<0.001}. ICI was associated with a lower adjusted hazard of death [HR =0.63; 95% CI: 0.52-0.75; P<0.001] compared to subsequent chemotherapy treatment. Conclusions: In this population-based study of older patients with NSCLC and SBM previously treated with chemotherapy, subsequent treatment with ICI was associated with improved survival compared to chemotherapy.

Operative planning for a functional precision medicine assay of recurrent high-grade glioma: illustrative case.

BACKGROUND: Functional precision medicine (FPM) represents a personalized and efficacious modality for treating malignant neoplasms. However, acquiring sufficient live tissue to perform FPM analyses is complicated by both difficult identification on imaging and radiation necrosis, particularly in cases of recurrence. The authors describe a case of planning biopsy trajectories for an FPM assay in a patient with recurrent high-grade glioma. OBSERVATIONS: A 25-year-old male with a history of recurrent high-grade glioma was scheduled for laser ablation and biopsy with ChemoID assaying after regions of potential recurrence were identified on follow-up imaging. Preoperative magnetic resonance (MR) spectroscopy of the regions showed areas of high choline/creatine ratios within lesions of radiation necrosis, which helped in planning the biopsy trajectories to selectively target malignancies for FPM analysis. ChemoID results showed high tumor susceptibility to lomustine, which was implemented as adjuvant therapy. LESSONS: FPM therapy in the setting of recurrence is complicated by radiation necrosis, which can present as malignancy on imaging and interfere with tissue acquisition during biopsy or resection. Thus, operative approaches should be carefully planned with the assistance of imaging modalities such as MR spectroscopy to better ensure effective tissue acquisition for accurate FPM analysis and to promote more definitive treatment of recurrence.

Laser interstitial thermal therapy for new and recurrent meningioma: a prospective and retrospective case series.

OBJECTIVE: Meningiomas are the most common primary brain tumors in adults and a subset are aggressive lesions resistant to standard therapies. Laser interstitial thermal therapy (LITT) has been successfully applied to other brain tumors, and recent work aims to explore the safety and long-term outcome experiences of LITT for both new and recurrent meningiomas. The authors' objective was to report safety and outcomes data of the largest cohort of LITT-treated meningioma patients to date. METHODS: Eight United States-based hospitals enrolled patients with meningioma in the Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System (LAANTERN) prospective multicenter registry and/or contributed additional retrospective enrollments for this cohort study. Demographic, procedural, safety, and outcomes data were collected and analyzed using standard statistical methods. RESULTS: Twenty adult patients (12 prospective and 8 retrospective) with LITT-targeted meningiomas were accrued. Patients underwent LITT for new (6 patients) and recurrent (14 patients) tumors (ranging from the 1st to 12th recurrence). The 30-day complication rate was 10%. Twenty percent of patients (4/20) had exhausted all other treatment options. Median length of follow-up was 1.3 years. One-third of new (2/6) and one-half of recurrent (7/14) meningiomas had disease progression during follow-up. One-year estimated local control (LC), progression-free survival, and overall survival rates were 55.3%, 48.4%, and 86.3%, respectively. In the 12 patients who had ≥ 91% ablative coverage, 1-year estimated LC was 61.4%. The complication rate was 10% (2/20), with 1 complication being transient and resolving postoperatively. CONCLUSIONS: This cohort study supports the safety of the procedure for this tumor type. LITT can offer a much-needed treatment option, especially for patients with multiply recurrent meningiomas who have limited remaining alternatives.

Bifunctional Inhibitor Reveals NEK2 as a Therapeutic Target and Regulator of Oncogenic Pathways in Lymphoma.

Expression of the serine/threonine kinase never in mitosis gene A (NIMA)-related kinase 2 (NEK2) is essential for entry into mitosis via its role in facilitating centrosome separation. Its overactivity can lead to tumorigenesis and drug resistance through the activation of several oncogenic pathways, including AKT. Although the cancer-enabling activities of NEK2 are documented in many malignancies, including correlations with poor survival in myeloma, breast, and non-small cell lung cancer, little is known about the role of NEK2 in lymphoma. Here, in tumors from patients with diffuse large B-cell lymphoma (DLBCL), the most common, aggressive non-Hodgkin lymphoma, we found a high abundance of NEK2 mRNA and protein associated with an inferior overall survival. Using our recently developed NEK2 inhibitor, NBI-961, we discovered that DLBCL cell lines and patient-derived cells exhibit a dependency on NEK2 for their viability. This compromised cell fitness was directly attributable to efficient NEK2 inhibition and proteasomal degradation by NBI-961. In a subset of particularly sensitive DLBCL cells, NBI-961 induced G2/mitosis arrest and apoptosis. In contrast, an existing indirect NEK2 inhibitor, INH154, did not prevent NEK2 autophosphorylation, induce NEK2 proteasomal degradation, or affect cell viability. Global proteomics and phospho-proteomics revealed that NEK2 orchestrates cell-cycle and apoptotic pathways through regulation of both known and new signaling molecules. We show the loss of NEK2-sensitized DLBCL to the chemotherapy agents, doxorubicin and vincristine, and effectively suppressed tumor growth in mice. These studies establish the oncogenic activity of NEK2 in DLBCL and set the foundation for development of anti-NEK2 therapeutic strategies in this frequently refractory and relapse-prone cancer.

Functional prediction of response to therapy prior to therapeutic intervention is associated with improved survival in patients with high-grade glioma.

Patients with high-grade glioma (HGG) have an extremely poor prognosis compounded by a lack of advancement in clinical care over the past few decades. Regardless of classification, most newly diagnosed patients receive the same treatment, radiation and temozolomide (RT/TMZ). We developed a functional precision oncology test that prospectively identifies individual patient's response to this treatment regimen. Tumor tissues isolated from patients with newly diagnosed HGG enrolled in 3D PREDICT REGISTRY were evaluated for response to chemotherapeutic agents using the 3D Predict™ Glioma test. Patients receiving RT/TMZ were followed for 2 years. Clinical outcomes including imaging, assessments, and biomarker measurements were compared to patient matched test-predicted therapy response. Median survival between test-predicted temozolomide responders and test-predicted temozolomide non-responders revealed a statistically significant increase in progression-free survival when using the test to predict response across multiple subgroups including HGG (5.8 months), glioblastoma (4.7 months), and MGMT unmethylated glioblastoma (4.7 months). Overall survival was also positively separated across the subgroups at 7.6, 5.1, and 6.3 months respectively. The strong correlation of 3D Predict Glioma test results with clinical outcomes demonstrates that this functional test is prognostic in patients treated with RT/TMZ and supports aligning clinical treatment to test-predicted response across varying HGG subgroups.