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1.
Semin Nephrol ; 44(1): 151503, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38519279

ABSTRACT

Post-transplant lymphoproliferative disorders (PTLDs) are a heterogenous set of unregulated lymphoid cell proliferations after organ or tissue transplant. A majority of cases are associated with the Epstein-Barr virus and higher intensity of pharmacologic immunosuppression. The clinical presentations are numerous. The diagnosis is ideally by histology, except in cases where the tumor is inaccessible to biopsy. While some pre-emptive therapies and treatment strategies are available have reasonable success are available, they do not eliminate the high morbidity and significant mortality after PTLD.


Subject(s)
Epstein-Barr Virus Infections , Lymphoproliferative Disorders , Humans , Lymphoproliferative Disorders/etiology , Epstein-Barr Virus Infections/complications , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Postoperative Complications/etiology , Kidney Transplantation/adverse effects , Herpesvirus 4, Human/isolation & purification , Organ Transplantation/adverse effects , Immunosuppression Therapy/adverse effects
2.
Nature ; 625(7996): 778-787, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38081297

ABSTRACT

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1-4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.


Subject(s)
Circulating Tumor DNA , Genome, Human , Genomics , Hodgkin Disease , Humans , Hodgkin Disease/blood , Hodgkin Disease/classification , Hodgkin Disease/diagnosis , Hodgkin Disease/genetics , Mutation , Reed-Sternberg Cells/metabolism , Tumor Microenvironment , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , Single-Cell Gene Expression Analysis , Genome, Human/genetics
4.
Best Pract Res Clin Haematol ; 36(1): 101442, 2023 03.
Article in English | MEDLINE | ID: mdl-36907635

ABSTRACT

The prognosis is dismal (2-year overall survival less than 25%) for childhood, adolescent, and young adult (CAYA) with relapsed and/or refractory (R/R) non-Hodgkin lymphoma (NHL). Novel targeted therapies are desperately needed for this poor-risk population. CD19, CD20, CD22, CD79a, CD38, CD30, LMP1 and LMP2 are attractive targets for immunotherapy in CAYA patients with R/R NHL. Novel anti-CD20 monoclonal antibodies, anti-CD38 monoclonal antibody, antibody drug conjugates and T and natural killer (NK)-cell bispecific and trispecific engagers are being investigated in the R/R setting and are changing the landscape of NHL therapy. A variety of cellular immunotherapies such as viral activated cytotoxic T-lymphocyte, chimeric antigen receptor (CAR) T-cells, NK and CAR NK-cells have been investigated and provide alternative options for CAYA patients with R/R NHL. Here, we provide an update and clinical practice guidance of utilizing these cellular and humoral immunotherapies in CAYA patients with R/R NHL.


Subject(s)
Antineoplastic Agents , Immunoconjugates , Lymphoma, Non-Hodgkin , Young Adult , Humans , Child , Adolescent , Lymphoma, Non-Hodgkin/drug therapy , Immunotherapy , Antineoplastic Agents/therapeutic use , Immunoconjugates/therapeutic use , Killer Cells, Natural/pathology , Immunotherapy, Adoptive , Antigens, CD19
5.
Blood Adv ; 7(13): 3225-3231, 2023 07 11.
Article in English | MEDLINE | ID: mdl-36897253

ABSTRACT

Outcomes for children and adolescents with relapsed and refractory Hodgkin lymphoma (HL) are poor, with ∼50% of patients experiencing a subsequent relapse. The anti-CD30 antibody-drug conjugate brentuximab vedotin improved progression-free survival (PFS) when used as consolidation after autologous stem cell transplantation (ASCT) in adults with high-risk relapsed/refractory HL. Data on brentuximab vedotin as consolidative therapy after ASCT in pediatric patients with HL are extremely limited, with data of only 11 patients reported in the literature. We performed a retrospective analysis of 67 pediatric patients who received brentuximab vedotin as consolidation therapy after ASCT for the treatment of relapsed/refractory HL to describe the experience of this regimen in the pediatric population. This is the largest cohort reported to date. We found that brentuximab vedotin was well tolerated with a safety profile similar to that of adult patients. With a median follow-up of 37 months, the 3-year PFS was 85%. These data suggest a potential role for the use of brentuximab vedotin as consolidation therapy after ASCT for children with relapsed/refractory HL.


Subject(s)
Hematopoietic Stem Cell Transplantation , Hodgkin Disease , Adult , Adolescent , Humans , Child , Brentuximab Vedotin/therapeutic use , Hodgkin Disease/drug therapy , Hodgkin Disease/pathology , Transplantation, Autologous , Retrospective Studies
6.
Br J Haematol ; 200(3): 297-305, 2023 02.
Article in English | MEDLINE | ID: mdl-36454546

ABSTRACT

Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.


Subject(s)
Burkitt Lymphoma , Lymphoproliferative Disorders , Organ Transplantation , Humans , Child , Infant , Child, Preschool , Adolescent , Burkitt Lymphoma/therapy , Burkitt Lymphoma/drug therapy , Organ Transplantation/adverse effects , Cyclophosphamide/therapeutic use , Rituximab/therapeutic use , Prednisone/therapeutic use , Lymphoproliferative Disorders/etiology , Treatment Outcome , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/adverse effects
7.
Cancer ; 129(5): 780-789, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36571557

ABSTRACT

BACKGROUND: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available. METHODS: A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. RESULTS: Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. CONCLUSIONS: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies. PLAIN LANGUAGE SUMMARY: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.


Subject(s)
Epstein-Barr Virus Infections , Lymphoma, Large B-Cell, Diffuse , Lymphoma, Non-Hodgkin , Lymphoproliferative Disorders , Myeloproliferative Disorders , Organ Transplantation , Child , Humans , Male , Female , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/epidemiology , Herpesvirus 4, Human , Prospective Studies , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/etiology , Lymphoma, Non-Hodgkin/complications , Lymphoma, Large B-Cell, Diffuse/pathology , Myeloproliferative Disorders/complications , Retrospective Studies , Organ Transplantation/adverse effects
8.
Front Oncol ; 12: 1033993, 2022.
Article in English | MEDLINE | ID: mdl-36523979

ABSTRACT

Clinical pathways are evidence-based tools that have been integrated into many aspects of pediatric hospital medicine and have proven effective at reducing in-hospital complications from a variety of diseases. Adaptation of similar tools for specific, high-risk patient populations in pediatric oncology has been slower, in part due to patient complexities and variations in management strategies. There are few published studies of clinical pathways for pediatric oncology patients. Pediatric patients with a new diagnosis of leukemia or lymphoma often present with one or more "oncologic emergencies" that require urgent intervention and deliberate multidisciplinary care to prevent significant consequences. Here, we present two clinical pathways that have recently been developed using a multidisciplinary approach at a single institution, intended for the care of patients who present with hyperleukocytosis or an anterior mediastinal mass. These clinical care pathways have provided a critical framework for the immediate care of these patients who are often admitted to the pediatric intensive care unit for initial management. The goal of the pathways is to facilitate multidisciplinary collaborations, expedite diagnosis, and streamline timely treatment initiation. Standardizing the care of high-risk pediatric oncology patients will ultimately decrease morbidity and mortality associated with these diseases to increase the potential for excellent outcomes.

9.
Med ; 3(11): 774-791.e7, 2022 11 11.
Article in English | MEDLINE | ID: mdl-36195086

ABSTRACT

BACKGROUND: Malignant rhabdoid tumors (MRTs) and Wilms' tumors (WTs) are rare and aggressive renal tumors of infants and young children comprising ∼5% of all pediatric cancers. MRTs are among the most genomically stable cancers, and although WTs are genomically heterogeneous, both generally lack therapeutically targetable genetic mutations. METHODS: Comparative protein activity analysis of MRTs (n = 68) and WTs (n = 132) across TCGA and TARGET cohorts, using metaVIPER, revealed elevated exportin 1 (XPO1) inferred activity. In vitro studies were performed on a panel of MRT and WT cell lines to evaluate effects on proliferation and cell-cycle progression following treatment with the selective XPO1 inhibitor selinexor. In vivo anti-tumor activity was assessed in patient-derived xenograft (PDX) models of MRTs and WTs. FINDINGS: metaVIPER analysis identified markedly aberrant activation of XPO1 in MRTs and WTs compared with other tumor types. All MRT and most WT cell lines demonstrated baseline, aberrant XPO1 activity with in vitro sensitivity to selinexor via cell-cycle arrest and induction of apoptosis. In vivo, XPO1 inhibitors significantly abrogated tumor growth in PDX models, inducing effective disease control with sustained treatment. Corroborating human relevance, we present a case report of a child with multiply relapsed WTs with prolonged disease control on selinexor. CONCLUSIONS: We report on a novel systems-biology-based comparative framework to identify non-genetically encoded vulnerabilities in genomically quiescent pediatric cancers. These results have provided preclinical rationale for investigation of XPO1 inhibitors in an upcoming investigator-initiated clinical trial of selinexor in children with MRTs and WTs and offer opportunities for exploration of inferred XPO1 activity as a potential predictive biomarker for response. FUNDING: This work was funded by CureSearch for Children's Cancer, Alan B. Slifka Foundation, NIH (U01 CA217858, S10 OD012351, and S10 OD021764), Michael's Miracle Cure, Hyundai Hope on Wheels, Cannonball Kids Cancer, Conquer Cancer the ASCO Foundation, Cycle for Survival, Paulie Strong Foundation, and the Grayson Fund.


Subject(s)
Kidney Neoplasms , Child , Humans , Child, Preschool , Cell Line, Tumor , Xenograft Model Antitumor Assays , Kidney Neoplasms/drug therapy , Exportin 1 Protein
12.
J Pediatr Hematol Oncol ; 43(2): e191-e194, 2021 03 01.
Article in English | MEDLINE | ID: mdl-31876780

ABSTRACT

We describe 6 pediatric patients (12 to 18 y) with relapsed or refractory Hodgkin lymphoma treated with consolidative Brentuximab vedotin (Bv) following reinduction chemotherapy and autologous stem cell transplantation. The progression-free survival after autologous stem cell transplantation was 12, 18, 22, 24, 30, and 30 months. Most patients tolerated Bv well although 2 patients developed grade 3 neuropathy that prevent them from completing the scheduled 16 doses of Bv. Consolidative Bv in children and adolescents, as currently recommended for adult patients with early relapsed or refractory Hodgkin lymphoma, is feasible but with some significant toxicities.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Brentuximab Vedotin/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Hodgkin Disease/therapy , Neoplasm Recurrence, Local/therapy , Adolescent , Child , Combined Modality Therapy , Consolidation Chemotherapy , Female , Follow-Up Studies , Hodgkin Disease/pathology , Humans , Male , Neoplasm Recurrence, Local/pathology , Prognosis
13.
Pediatr Blood Cancer ; 67(9): e28361, 2020 09.
Article in English | MEDLINE | ID: mdl-32672879

ABSTRACT

Waldeyer's ring (WR) involvement in pediatric Hodgkin lymphoma (HL) is extremely rare and criteria for determining involvement and response to treatment are unclear. The international Staging, Evaluation, and Response Criteria Harmonization for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) Group performed a systematic review of the literature in search of involvement or response criteria, or evidence to support specific criteria. Only 166 cases of HL with WR involvement were reported in the literature, 7 of which were pediatric. To date no standardized diagnostic or response assessment criteria are available. Given the paucity of evidence, using a modified Delphi survey technique, expert consensus statements were developed by the SEARCH group to allow for a more consistent definition of disease and response evaluation related to this rare site of involvement among pediatric oncologists. The available evidence and expert consensus statements are summarized.


Subject(s)
Hodgkin Disease/pathology , Oropharynx/diagnostic imaging , Oropharynx/pathology , Adenoids/pathology , Expert Testimony , Fluorodeoxyglucose F18 , Hodgkin Disease/diagnostic imaging , Humans , Palate, Soft/pathology , Palatine Tonsil/pathology , Positron-Emission Tomography , Tongue/pathology
14.
Pediatr Blood Cancer ; 65(12): e27375, 2018 12.
Article in English | MEDLINE | ID: mdl-30277639

ABSTRACT

PURPOSE: Optimal management of patients with intermediate-risk lymphocyte-predominant Hodgkin lymphoma (LPHL) is unclear due to their small numbers in most clinical trials. Children's Oncology Group AHOD0031, a randomized phase III trial of pediatric patients with intermediate-risk Hodgkin lymphoma (HL), included patients with LPHL. We report the outcomes of these patients and present directions for future therapeutic strategies. PROCEDURE: Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) followed by response evaluation. Slow early responders were randomized to two additional ABVE-PC cycles ± two dexamethasone, etoposide, cisplatin, and cytarabine cycles and all received involved field radiotherapy (IFRT). Rapid early responders (RERs) received two additional ABVE-PC cycles. RERs with complete response (CR) were randomized to IFRT or no further therapy. RERs without CR received IFRT. RESULTS: Ninety-six (5.6%) of 1711 patients on AHOD0031 had LPHL. Patients with LPHL were more likely to achieve RER (93.6% vs. 81.0%; P = 0.002) and CR (74.2% vs. 49.3%; P = 0.000005) following chemotherapy compared with patients with classical HL. Five-year event-free survival (EFS) was superior in patients with LPHL (92.2%) versus classical HL (83.5%) (P = 0.04), without difference in overall survival (OS). Among RERs with CR following chemotherapy (n = 33), there was no difference in EFS or OS between those randomized to receive or not receive IFRT. CONCLUSION: Children and adolescents with intermediate-risk LPHL represent ideal candidates for response-adapted therapy based on their favorable outcomes. The majority of patients treated with the ABVE-PC backbone achieve RER with CR status and can be treated successfully without IFRT.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chemoradiotherapy , Hodgkin Disease/mortality , Hodgkin Disease/therapy , Adolescent , Bleomycin/administration & dosage , Child , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Humans , Male , Prednisolone/administration & dosage , Risk Factors , Survival Rate , Vincristine/administration & dosage
16.
Glob Pediatr Health ; 5: 2333794X18774970, 2018.
Article in English | MEDLINE | ID: mdl-29785408

ABSTRACT

Objectives. The prevalence of stroke among children with sickle cell disease (SCD) in sub-Saharan Africa was systematically reviewed. Methods. Comprehensive searches of PubMed, Embase, and Web of Science were performed for articles published between 1980 and 2016 (English or French) reporting stroke prevalence. Using preselected inclusion criteria, titles and abstracts were screened and full-text articles were reviewed. Results. Ten full-text articles met selection criteria. Cross-sectional clinic-based data reported 2.9% to 16.9% stroke prevalence among children with SCD. Using available sickle gene frequencies by country, estimated pediatric mortality, and fixed- and random-effects model, the number of affected individuals is projected as 29 800 (95% confidence interval = 25 571-34 027) and 59 732 (37 004-82 460), respectively. Conclusion. Systematic review enabled the estimation of the number of children with SCD stroke in sub-Saharan Africa. High disease mortality, inaccurate diagnosis, and regional variability of risk hamper more precise estimates. Adopting standardized stroke assessments may provide more accurate determination of numbers affected to inform preventive interventions.

17.
Front Pediatr ; 5: 265, 2017.
Article in English | MEDLINE | ID: mdl-29312904

ABSTRACT

BACKGROUND: The advent of comprehensive genomic profiling has markedly advanced the understanding of the biology of pediatric hematological malignancies, however, its application to clinical care is still unclear. We present our experience integrating genomic data into the clinical management of children with high-risk hematologic malignancies and blood disorders and describe the broad impact that genomic profiling has in multiple aspects of patient care. METHODS: The Precision in Pediatric Sequencing Program at Columbia University Medical Center instituted prospective clinical next-generation sequencing (NGS) for high-risk malignancies and blood disorders. Testing included cancer whole exome sequencing (WES) of matched tumor-normal samples or targeted sequencing of 467 cancer-associated genes, when sample adequacy was a concern, and tumor transcriptome (RNA-seq). A multidisciplinary molecular tumor board conducted interpretation of results and final tiered reports were transmitted to the electronic medical record according to patient preferences. RESULTS: Sixty-nine samples from 56 patients with high-risk hematologic malignancies and blood disorders were sequenced. Patients carried diagnoses of myeloid malignancy (n = 25), lymphoid malignancy (n = 25), or histiocytic disorder (n = 6). Six patients had only constitutional WES, performed for a suspicion of an inherited predisposition for their disease. For the remaining 50 patients, tumor was sequenced with matched normal tissue when available. The mean number of somatic variants per sample was low across the different disease categories (2.85 variants/sample). Interestingly, a gene fusion was identified by RNA-seq in 58% of samples who had adequate RNA available for testing. Molecular profiling of tumor tissue led to clinically impactful findings in 90% of patients. Forty patients (80%) had at least one targetable gene variant or fusion identified in their tumor tissue; however, only seven received targeted therapy. Importantly, NGS findings contributed to the refinement of diagnosis and prognosis for 34% of patients. Known or likely pathogenic germline alterations were discovered in 24% of patients involving cancer predisposition genes in 12% of cases. CONCLUSION: Incorporating whole exome and transcriptome profiling of tumor and normal tissue into clinical practice is feasible, and the value that comprehensive testing provides extends beyond the ability to target-specific mutations.

18.
Genome Med ; 8(1): 116, 2016 10 31.
Article in English | MEDLINE | ID: mdl-27799065

ABSTRACT

BACKGROUND: Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities. METHODS: We utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient's tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options. RESULTS: WES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK. CONCLUSIONS: This clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/drug therapy , Carcinoma/genetics , Genomics/methods , Rare Diseases/drug therapy , Rare Diseases/genetics , Adolescent , Animals , Carboplatin/adverse effects , Carcinoma/diagnostic imaging , DNA Mutational Analysis , Etoposide/adverse effects , Fatal Outcome , Humans , Male , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Paclitaxel/adverse effects , Rare Diseases/diagnostic imaging , Scalp/drug effects , Scalp/metabolism , Scalp/pathology , Xenograft Model Antitumor Assays
19.
Biochem J ; 455(1): 15-25, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23815625

ABSTRACT

Neuronal apoptotic death generally requires de novo transcription, and activation of the transcription factor c-Jun has been shown to be necessary in multiple neuronal death paradigms. Caspase-2 has been implicated in death of neuronal and non-neuronal cells, but its relationship to transcriptional activation has not been clearly elucidated. In the present study, using two different neuronal apoptotic paradigms, ß-amyloid treatment and NGF (nerve growth factor) withdrawal, we examined the hierarchical role of caspase-2 activation in the transcriptional control of neuron death. Both paradigms induce rapid activation of caspase-2 as well as activation of the transcription factor c-Jun and subsequent induction of the pro-apoptotic BH3 (Bcl-homology domain 3)-only protein Bim (Bcl-2-interacting mediator of cell death). Caspase-2 activation is dependent on the adaptor protein RAIDD {RIP (receptor-interacting protein)-associated ICH-1 [ICE (interleukin-1ß-converting enzyme)/CED-3 (cell-death determining 3) homologue 1] protein with a death domain}, and both caspase-2 and RAIDD are required for c-Jun activation and Bim induction. The present study thus shows that rapid caspase-2 activation is essential for c-Jun activation and Bim induction in neurons subjected to apoptotic stimuli. This places caspase-2 at an apical position in the apoptotic cascade and demonstrates for the first time that caspase-2 can regulate transcription.


Subject(s)
Apoptosis Regulatory Proteins/genetics , CRADD Signaling Adaptor Protein/genetics , Caspase 2/genetics , Membrane Proteins/genetics , Neurons/metabolism , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins/genetics , Transcriptional Activation/drug effects , Amyloid beta-Peptides/pharmacology , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Bcl-2-Like Protein 11 , CRADD Signaling Adaptor Protein/metabolism , Caspase 2/metabolism , Fetus , Membrane Proteins/metabolism , Nerve Growth Factor/deficiency , Neurons/cytology , Neurons/drug effects , Primary Cell Culture , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-jun/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Transcription, Genetic/drug effects
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