Publications by authors named "Kelly C Goldsmith"

17 Publications

  • Page 1 of 1

YAP-Mediated Repression of HRK Regulates Tumor Growth, Therapy Response, and Survival Under Tumor Environmental Stress in Neuroblastoma.

Cancer Res 2020 11 8;80(21):4741-4753. Epub 2020 Sep 8.

Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.

Following chemotherapy and relapse, high-risk neuroblastoma tumors harbor more genomic alterations than at diagnosis, including increased transcriptional activity of the Yes-associated protein (YAP), a key downstream component of the Hippo signaling network. Although YAP has been implicated in many cancer types, its functional role in the aggressive pediatric cancer neuroblastoma is not well-characterized. In this study, we performed genetic manipulation of YAP in human-derived neuroblastoma cell lines to investigate YAP function in key aspects of the malignant phenotype, including mesenchymal properties, tumor growth, chemotherapy response, and MEK inhibitor response. Standard cytotoxic therapy induced YAP expression and transcriptional activity in patient-derived xenografts treated , which may contribute to neuroblastoma recurrence. Moreover, YAP promoted a mesenchymal phenotype in high-risk neuroblastoma that modulated tumor growth and therapy resistance . Finally, the BH3-only protein, Harakiri (HRK), was identified as a novel target inhibited by YAP, which, when suppressed, prevented apoptosis in response to nutrient deprivation and promoted tumor aggression, chemotherapy resistance, and MEK inhibitor resistance . Collectively, these findings suggest that YAP inhibition may improve chemotherapy response in patients with neuroblastoma via its regulation of HRK, thus providing a critical strategic complement to MEK inhibitor therapy. SIGNIFICANCE: This study identifies HRK as a novel tumor suppressor in neuroblastoma and suggests dual MEK and YAP inhibition as a potential therapeutic strategy in -hyperactivated neuroblastomas.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0025DOI Listing
November 2020

A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors.

Pediatr Blood Cancer 2020 04 25;67(4):e28134. Epub 2019 Dec 25.

Division of Pediatric Hematology/Oncology and Bone Marrow Transplantation, Nemours Children's Specialty Care and Wolfson Children's Hospital, Jacksonville, Florida.

Background/purpose: To determine the maximum tolerated dose, toxicities, and response of sirolimus combined with oral metronomic therapy in pediatric patients with recurrent and refractory solid and brain tumors.

Procedure: Patients younger than 30 years of age with recurrent, refractory, or high-risk solid and brain tumors were eligible. Patients received six-week cycles of sirolimus with twice daily celecoxib, and alternating etoposide and cyclophosphamide every three weeks, with Bayesian dose escalation over four dose levels (NCT01331135).

Results: Eighteen patients were enrolled: four on dose level (DL) 1, four on DL2, eight on DL3, and two on DL4. Diagnoses included solid tumors (Ewing sarcoma, osteosarcoma, malignant peripheral nerve sheath tumor, rhabdoid tumor, retinoblastoma) and brain tumors (glioblastoma multiforme [GBM], diffuse intrinsic pontine glioma, high-grade glioma [HGG], medulloblastoma, ependymoma, anaplastic astrocytoma, low-grade infiltrative astrocytoma, primitive neuroectodermal tumor, nongerminomatous germ cell tumor]. One dose-limiting toxicity (DLT; grade 4 neutropenia) was observed on DL2, two DLTs (grade 3 abdominal pain and grade 3 mucositis) on DL3, and two DLTs (grade 3 dehydration and grade 3 mucositis) on DL4. The recommended phase II dose of sirolimus was 2 mg/m (DL3). Best response was stable disease (SD) in eight patients, and partial response (PR) in one patient with GBM. A patient with HGG was removed from the study with SD and developed PR without further therapy. Western blot analysis showed inhibition of phospho-S6 kinase in all patients during the first cycle of therapy.

Conclusion: The combination of sirolimus with metronomic chemotherapy is well tolerated in children. A phase II trial of this combination is ongoing.
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http://dx.doi.org/10.1002/pbc.28134DOI Listing
April 2020

Multidisciplinary Care of Adult Wilms' Tumor During Pregnancy: A Case Report and Review of the Literature.

Clin Genitourin Cancer 2020 02 2;18(1):e1-e4. Epub 2019 Oct 2.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Winship Cancer Institute of Emory University, Atlanta, GA. Electronic address:

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http://dx.doi.org/10.1016/j.clgc.2019.09.021DOI Listing
February 2020

Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model.

Oncoimmunology 2019;8(8):1593804. Epub 2019 May 27.

Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.

An effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with temozolomide and irinotecan, supporting a role for chemo-immunotherapy in NB. γδ T cells are an attractive anti-tumor immunotherapy because of their direct cytotoxic activity mediated through cell surface receptors NKG2D and CD16. NKG2D facilitates the innate recognition of stress-induced ligands whereas CD16 recognizes antibody bound to tumors and activates mechanisms of antibody-dependent cellular cytotoxicity (ADCC). This study demonstrates an efficient method for expanding and storing γδ T cells from NB patient-derived apheresis products at clinically relevant amounts. The expanded patient-derived γδ T cells were cytotoxic against the K562 cell line and multiple NB cell lines. Combining γδ T cells with dinutuximab led to a 30% increase in tumor cell lysis compared to γδ T cells alone. Furthermore, low-dose temozolomide in combination with expanded γδ T cells and dinutuximab resulted in increased IFNγ secretion and increased γδ T-cell surface expression of FasL and CD107a. IMR5 NB cell line xenografts established subcutaneously in NSG mice were treated with a regimen of dinutuximab, temozolomide, and γδ T cells. This combination caused targeted killing of NB xenografts in vivo, reducing tumor burden and prolonging survival. These data support the continued preclinical testing of dinutuximab and temozolomide in conjunction with γδ T-cell immunotherapy for patients with recurrent/refractory NB.
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http://dx.doi.org/10.1080/2162402X.2019.1593804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682349PMC
May 2019

Mentors' perspectives on the successes and challenges of mentoring in the COG Young Investigator mentorship program: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2019 10 16;66(10):e27920. Epub 2019 Jul 16.

Division of Pediatric Hematology-Oncology, Children's Hospital of Los Angeles, Los Angeles, California.

Background: Identification and development of young investigators (YI) is critical to the long-term success of research organizations. In 2004, the Children's Oncology Group (COG) created a mentorship program to foster the career development of YIs (faculty <10 years from initial appointment). This study sought to assess mentors' long-term assessment of this program.

Procedure: In 2018, 101 past or current mentors in the COG YI mentorship program completed an online survey. Statistical comparisons were made with the Kruskal-Walis test.

Results: The response rate was 74.2%. As some mentors had multiple mentees, we report on 138 total mentee-mentor pairs. Mentors were 57.4% male, and mentees were 39.1% male. Mentors rated being mentored as a YI as important with a median rating of 90 on a scale of 1-100, interquartile range (IQR) 80-100. Most mentors reported that being mentored themselves helped their own success within COG (78.2%) and with their overall career development (92.1%). Most mentors enjoyed serving in the program (72.3%) and the median success rating (on a scale of 1-100) across the mentor-mentee pairings was 75, IQR 39-90. Success ratings did not differ by mentor/mentee gender, but improved with increased frequency of mentor-mentee interactions (P < .001). Mentor-mentee pairs who set initial goals reported higher success ratings than those who did not (P < .001). Tangible successes included current mentee COG committee involvement (45.7%), ongoing mentor-mentee collaboration (53.6%), and co-authored manuscript publication (38.4%).

Conclusion: These data indicate that mentorship is important for successful professional development. Long-term mentoring success improves when mentors and mentees set goals upfront and meet frequently.
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http://dx.doi.org/10.1002/pbc.27920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707882PMC
October 2019

Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma.

Nat Commun 2019 06 3;10(1):2410. Epub 2019 Jun 3.

Department of Pediatrics, Neuro-Oncology Division and Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, 30322, GA, United States.

Medulloblastoma, which is the most common malignant paediatric brain tumour, has a 70% survival rate, but standard treatments often lead to devastating life-long side effects and recurrence is fatal. One of the emerging strategies in the search for treatments is to determine the roles of tumour microenvironment cells in the growth and maintenance of tumours. The most attractive target is tumour-associated macrophages (TAMs), which are abundantly present in the Sonic Hedgehog (SHH) subgroup of medulloblastoma. Here, we report an unexpected beneficial role of TAMs in SHH medulloblastoma. In human patients, decreased macrophage number is correlated with significantly poorer outcome. We confirm macrophage anti-tumoural behaviour in both ex vivo and in vivo murine models of SHH medulloblastoma. Taken together, our findings suggest that macrophages play a positive role by impairing tumour growth in medulloblastoma, in contrast to the pro-tumoural role played by TAMs in glioblastoma, another common brain tumour.
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http://dx.doi.org/10.1038/s41467-019-10458-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546707PMC
June 2019

Hyperleukocytosis in infant acute leukemia: a role for manual exchange transfusion for leukoreduction.

Transfusion 2018 05 4;58(5):1149-1156. Epub 2018 Feb 4.

Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.

Background: Hyperleukocytosis is a serious, life-threatening complication of pediatric acute leukemia that can cause neurologic injury, pulmonary leukostasis, metabolic derangements, and coagulopathy. Acute leukemia has the highest risk of mortality and morbidity at presentation when associated with hyperleukocytosis. Infant leukemia presents unique challenges and treatment considerations due to the disease itself and size and overall health of the patient. While medical management of hyperleukocytosis in older patients with acute leukemia has been described, including cytoreductive procedures with automated leukapheresis (AL) or manual whole blood (WB) exchange transfusion, very little data exist for standardized management of hyperleukocytosis in infant leukemia patients.

Case Reports: We describe four cases of infant acute leukemia presenting with hyperleukocytosis and leukostasis who each received manual WB exchange transfusions in conjunction with induction chemotherapy and review the existing literature on the use of procedural leukoreduction in infants with hyperleukocytosis. Special attention is given to challenges and technical aspects of leukapheresis in infants: when to perform manual WB exchange versus AL, optimal vascular access, blood product selection, exchange rates, and the monitoring for complications. Using published cases, we outline benefits versus risks of manual WB exchange and AL in infants less than 10 kg.

Conclusion: If providers perform procedural leukoreduction, the literature and our experience demonstrate manual WB exchange transfusion is favored over AL in infants less than 10 kg because of technical and complication risks associated with AL. Additional studies are needed to understand the impact of cytoreduction on long-term outcomes.
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http://dx.doi.org/10.1111/trf.14512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912979PMC
May 2018

Favorable Local Control From Consolidative Radiation Therapy in High-Risk Neuroblastoma Despite Gross Residual Disease, Positive Margins, or Nodal Involvement.

Int J Radiat Oncol Biol Phys 2017 03 27;97(4):806-812. Epub 2016 Nov 27.

Department of Radiation Oncology, Emory University, Atlanta, Georgia; Winship Cancer Institute, Emory University, Atlanta, Georgia.

Purpose: To report the influence of radiation therapy (RT) dose and surgical pathology variables on disease control and overall survival (OS) in patients treated for high-risk neuroblastoma at a single institution.

Methods And Materials: We conducted a retrospective study of 67 high-risk neuroblastoma patients who received RT as part of definitive management from January 2003 until May 2014.

Results: At a median follow-up of 4.5 years, 26 patients (38.8%) failed distantly; 4 of these patients also failed locally. One patient progressed locally without distant failure. Local control was 92.5%, and total disease control was 59.5%. No benefit was demonstrated for RT doses over 21.6 Gy with respect to local relapse-free survival (P=.55), disease-free survival (P=.22), or OS (P=.72). With respect to local relapse-free survival, disease-free survival, and OS, no disadvantage was seen for positive lymph nodes on surgical pathology, positive surgical margins, or gross residual disease. Of the patients with gross residual disease, 75% (6 of 8) went on to have no evidence of disease at time of last follow-up, and the 2 patients who failed did so distantly.

Conclusions: Patients with high-risk neuroblastoma in this series maintained excellent local control, with no benefit demonstrated for radiation doses over 21.6 Gy, and no disadvantage demonstrated for gross residual disease after surgery, positive surgical margins, or pathologic lymph node positivity. Though the limitations of a retrospective review for an uncommon disease must be kept in mind, with small numbers in some of the subgroups, it seems that dose escalation should be considered only in exceptional circumstances.
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http://dx.doi.org/10.1016/j.ijrobp.2016.11.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502807PMC
March 2017

Concurrent myeloid sarcoma, atypical teratoid/rhabdoid tumor, and hypereosinophilia in an infant with a germline SMARCB1 mutation.

Pediatr Blood Cancer 2017 Sep 23;64(9). Epub 2017 Jan 23.

Division of Hematology/Oncology, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia.

We report a 1-year-old female child presenting with hypereosinophilia who was found to have concurrent myeloid sarcoma and a central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT). She was later found to have a germline mutation in SMARCB1. Concurrent hematologic malignancy and CNS AT/RT have not previously been described in the context of a SMARCB1 loss-of-function germline mutation.
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http://dx.doi.org/10.1002/pbc.26460DOI Listing
September 2017

Phase II evaluation of sunitinib in the treatment of recurrent or refractory high-grade glioma or ependymoma in children: a children's Oncology Group Study ACNS1021.

Cancer Med 2016 07 25;5(7):1416-24. Epub 2016 Apr 25.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105.

Sunitinib malate is a small multi-targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor (KIT), which are highly expressed by some high-grade brain tumors. We conducted a phase II study to estimate the efficacy and further characterize the pharmacokinetics of sunitinib in pediatric patients with recurrent or refractory high-grade glioma (Stratum A) or ependymoma (Stratum B). This was a prospective, multicenter Phase II trial conducted through the Children's Oncology Group (ClinicalTrials.gov Identifier NCT01462695). Sunitinib, 15 mg/m2, was orally administered once daily for 4 weeks every 6 weeks. The safety and tolerability of sunitinib, an estimate of progression-free survival (PFS), analyses of sunitinib pharmacokinetics (PK) and pharmacodynamics modulation of plasma VEGF and VEGFR2 were also assessed. Thirty eligible patients (17 patients on Stratum A, 13 patients on Stratum B) were enrolled and 29 patients were evaluable for response. Sunitinib was reasonably well tolerated in children with recurrent ependymoma or high-grade glioma. Most adverse events were of mild-to-moderate severity and manageable with supportive treatment. While there was a statistically significant modulation of plasma VEGFR2 with sunitinib exposure, there were no sustained tumor responses. Both strata were closed at time of planned interim analysis as there was not sufficient efficacy associated with sunitinib in children with recurrent brain tumors. Sunitinib was well tolerated in children and young adults with recurrent high-grade glioma or ependymoma but had no single agent objective antitumor activity in these patients.
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http://dx.doi.org/10.1002/cam4.713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944867PMC
July 2016

Select Bcl-2 antagonism restores chemotherapy sensitivity in high-risk neuroblastoma.

BMC Cancer 2016 Feb 13;16:97. Epub 2016 Feb 13.

Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, 30322, USA.

Background: Pediatric patients with high-risk neuroblastoma (HR NB) often fail to respond to upfront intensive multimodal therapy. Tumor-acquired suppression of apoptosis contributes to therapy resistance. Many HR NB tumors depend on the anti-apoptotic protein Bcl-2 for survival, through Bcl-2 sequestration and inhibition of the pro-apoptotic protein, Bim. Bcl-2 dependent xenografts derived from aggressive human NB tumors are cured with a combination of cyclophosphamide and ABT-737, a Bcl-2/Bcl-XL/Bcl-w small molecule antagonist. The oral analogue to ABT-737, Navitoclax (ABT-263), clinically causes an immediate drop in peripheral platelet counts as mature platelets depend on Bcl-xL for survival. This led to the creation of a Bcl-2 selective inhibitor, ABT-199 (Venetoclax). A Phase I trial of ABT-199 in CLL showed remarkable antitumor activity and stable patient platelet counts. Given Bcl-XL does not play a role in HR NB survival, we hypothesized that ABT-199 would be equally potent against HR NB.

Methods: Cytotoxicity and apoptosis were measured in human derived NB cell lines exposed to ABT-199 combinations. Co-Immunoprecipitation evaluated Bim displacement from Bcl-2, following ABT-199. Murine xenografts of NB cell lines were grown and then exposed to a 14-day course of ABT-199 alone and with cyclophosphamide.

Results: Bcl-2 dependent NB cell lines are exquisitely sensitive to ABT-199 (IC50 1.5-5 nM) in vitro, where Mcl-1 dependent NBs are completely resistant. Treatment with ABT-199 displaces Bim from Bcl-2 in NB to activate caspase 3, confirming the restoration of mitochondrial apoptosis. Murine xenografts of Mcl-1 and Bcl-2 dependent NBs were treated with a two-week course of ABT-199, cyclophosphamide, or ABT-199/cyclophosphamide combination. Mcl-1 dependent tumors did not respond to ABT-199 alone and showed no significant difference in time to tumor progression between chemotherapy alone or ABT-199/cyclophosphamide combination. In contrast, Bcl-2 dependent xenografts responded to ABT-199 alone and had sustained complete remission (CR) to the ABT-199/cyclophosphamide combination, with one recurrent tumor maintaining Bcl-2 dependence and obtaining a second CR after a second course of therapy.

Conclusion: HR NB patients are often thrombocytopenic at relapse, raising concerns for therapies like ABT-263 despite its HR NB tumor targeting potential. Our data confirms that Bcl-2 selective inhibitors like ABT-199 are equally potent in HR NB in vitro and in vivo and given their lack of platelet toxicity, should be translated into the clinic for HR NB.
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http://dx.doi.org/10.1186/s12885-016-2129-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752777PMC
February 2016

EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma.

Cancer Biol Ther 2015 ;16(2):276-86

a Division of Hematology/Oncology; Aflac Children's Cancer and Blood Disorders Center ; Children's Healthcare of Atlanta ; Atlanta , GA USA.

The pediatric solid tumor neuroblastoma (NB) often depends on the anti-apoptotic protein, Mcl(-)1, for survival through Mcl(-)1 sequestration of pro-apoptotic Bim. High affinity Mcl(-)1 inhibitors currently do not exist such that novel methods to inhibit Mcl(-)1 clinically are in high demand. Receptor tyrosine kinases (RTK) regulate Mcl(-)1 in many cancers and play a role in NB survival, yet how they regulate Bcl(-)2 family interactions in NB is unknown. We found that NB cell lines derived to resist the Bcl(-)2/-xl/-w antagonist, ABT-737, acquire a dependence on Mcl(-)1 and show increased expression and activation of the RTK, EGFR. Mcl(-)1 dependent NB cell lines derived at diagnosis and from the same tumor following relapse also have increased EGFR expression compared to those dependent on Bcl(-)2. Inhibition of EGFR by shRNA or erlotinib in Mcl(-)1 dependent NBs disrupts Bim binding to Mcl(-)1 and enhances its affinity for Bcl(-)2, restoring sensitivity to ABT-737 as well as cytotoxics in vitro. Mechanistically treatment of NBs with small molecule inhibitors of EGFR (erlotinib, cetuximab) and ERK (U0126) increases Noxa expression and dephosphorylates Bim to promote Bim binding to Bcl(-)2. Thus, EGFR regulates Mcl(-)1 dependence in high-risk NB via ERK-mediated phosphorylation of Bim such that EGFR/ERK inhibition renders Mcl(-)1 dependent tumors now reliant on Bcl(-)2. Clinically, EGFR inhibitors are ineffective as single agent compounds in patients with recurrent NB, likely due to this transferred survival dependence to Bcl(-)2. Likewise, EGFR or ERK inhibitors warrant further testing in combination with Bcl(-)2 antagonists in vivo as a novel future combination to overcome therapy resistance in the clinic.
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http://dx.doi.org/10.1080/15384047.2014.1002333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622539PMC
November 2015

Mitochondrial Bcl-2 family dynamics define therapy response and resistance in neuroblastoma.

Cancer Res 2012 May;72(10):2565-77

Division of Hematology/Oncology, Aflac Children's Cancer Center, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.

Neuroblastoma is a childhood tumor in which transient therapeutic responses are typically followed by recurrence with lethal chemoresistant disease. In this study, we characterized the apoptotic responses in diverse neuroblastomas using an unbiased mitochondrial functional assay. We defined the apoptotic set point of neuroblastomas using responses to distinct BH3 death domains providing a BH3 response profile and directly confirmed survival dependencies. We found that viable neuroblastoma cells and primary tumors are primed for death with tonic sequestration of Bim, a direct activator of apoptosis, by either Bcl-2 or Mcl-1, providing a survival dependency that predicts the activity of Bcl-2 antagonists. The Bcl-2/Bcl-xL/Bcl-w inhibitor ABT-737 showed single-agent activity against only Bim:Bcl-2 primed tumor xenografts. Durable complete regressions were achieved in combination with noncurative chemotherapy even for highest risk molecular subtypes with MYCN amplification and activating ALK mutations. Furthermore, the use of unique isogenic cell lines from patients at diagnosis and at the time of relapse showed that therapy resistance was not mediated by upregulation of Bcl-2 homologues or loss of Bim priming, but by repressed Bak/Bax activation. Together, our findings provide a classification system that identifies tumors with clinical responses to Bcl-2 antagonists, defines Mcl-1 as the principal mediator of Bcl-2 antagonist resistance at diagnosis, and isolates the therapy resistant phenotype to the mitochondria.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-3603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354953PMC
May 2012

Mcl1 downregulation sensitizes neuroblastoma to cytotoxic chemotherapy and small molecule Bcl2-family antagonists.

Cancer Biol Ther 2009 Aug 8;8(16):1587-95. Epub 2009 Aug 8.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.

Neuroblastoma (NB) is a common, highly lethal pediatric cancer, with treatment failures largely attributable to the emergence of chemoresistance. The pro-survival Bcl2 homology (BH) proteins critically regulate apoptosis, and may represent important therapeutic targets for restoring drug sensitivity in NB. We used a human NB tumor tissue microarray to survey the expression of pro-survival BH proteins Mcl1 and Bcl2, and correlated expression to clinical prognostic factors and survival. Primary NB tumors heterogeneously expressed Mcl1 or Bcl2, with high expression correlating to high-risk phenotype. Co-expression is infrequent (11%), but correlates to reduced survival. Using RNA interference, we investigated the functional relevance of Mcl1 and Bcl2 in high-risk NB cell lines (SK-N-AS, IMR-5, NLF). Mcl1 knockdown induced apoptosis in all NB cell lines, while Bcl2 knockdown inhibited only NLF, suggesting functional heterogeneity. Finally, we determined the relevance of Mcl1 in resistance to conventional chemotherapy (etoposide, doxorubicin) and small molecule Bcl2-family antagonists (ABT-737 and AT-101). Mcl1 silencing augmented sensitivity to chemotherapeutics 2- to 300-fold, while Bcl2 silencing did not, even in Bcl2-sensitive NLF cells. Resistance to ABT-737, which targets Bcl2/-w/-x, was overcome by Mcl1 knockdown. AT-101, which also neutralizes Mcl1, had single-agent cytotoxicity, further augmented by Mcl1 knockdown. In conclusion, Mcl1 appears a predominant pro-survival protein contributing to chemoresistance in NB, and Mcl1 inactivation may represent a novel therapeutic strategy. Optimization of compounds with higher Mcl1 affinity, or combination with additional Mcl1 antagonists, may enhance the clinical utility of this approach.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770183PMC
http://dx.doi.org/10.4161/cbt.8.16.8964DOI Listing
August 2009

Small-molecule BH3 mimetics to antagonize Bcl-2-homolog survival functions in cancer.

Curr Opin Investig Drugs 2009 Jun;10(6):559-71

The Children's Hospital of Philadelphia, Division of Oncology, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA.

Cancer arises through genetic alterations that improve cellular fitness and increase autonomy. These alterations, in addition to those invoked by genomic, metabolic and mechanical stressors, activate checkpoints that cancer cells must circumvent, including mitochondrial apoptosis. Thus, there is selective pressure to bypass apoptotic signaling in cancer cells, and this process is largely governed by Bcl-2 homology (BH) proteins. Given the primacy of the mitochondrial apoptosis checkpoint, it is surprising that the integrity of the apoptotic machinery is preserved in most cancers. Instead, it is the threshold for activating cell death that is elevated in cancer cells to provide a survival bias. Therapeutic opportunities are emerging as the roles for BH proteins are elucidated in normal and cancer cells. This review discusses small-molecule BH3 mimetics for the restoration of cancer-cell sensitivity to apoptotic stressors. Neuroblastoma, a lethal childhood tumor in which emergent therapy resistance is common, is presented to provide a model for the rational integration of BH3 mimetics into the clinic.
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June 2009

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS).

Blood 2006 Sep 6;108(6):1965-71. Epub 2006 Jun 6.

Divisions of Oncology and Hematology, Children's Hospital of Philadelphia, ARC 902, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.
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http://dx.doi.org/10.1182/blood-2006-01-010124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895548PMC
September 2006

Targeting programmed cell death pathways with experimental therapeutics: opportunities in high-risk neuroblastoma.

Cancer Lett 2005 Oct;228(1-2):133-41

Division of Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 9 North ARC, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA.

Neuroblastoma is a pediatric solid tumor with high morbidity and mortality in association with particular high-risk biological and clinical features (such as MYCN proto-oncogene amplification or advanced tumor stage). Such high-risk neuroblastomas may be initially responsive to cytoreductive therapies, yet the majority will ultimately demonstrate de novo or acquired chemoresistance leading to tumor progression and death. Insight into the genetic alterations responsible for these phenotypes are beginning to be gained, and subversion of inherent programmed cell death pathways is a common theme. Intact apoptosis pathways protect cells against neoplastic transformation and provide the mechanisms by which cytotoxic agents exert their effects. When these pathways are abolished through alterations in the cell death machinery, they complement deregulated oncogenes to promote tumor initiation and therapy resistance. Currently, therapeutic intensity for high-risk neuroblastoma has been advanced to near-tolerance with only modest gains in survival, and it is likely that further improvements in outcome will require innovative approaches that target key regulatory pathways that potentiate currently available therapies. Efforts to abrogate the cancer cell 'survival bias' engendered by alterations in death pathways are now a major focus in experimental cancer therapeutics, and their application to the problem of high-risk neuroblastoma form the basis of this review. These include agents that activate death receptors (TRAIL-agonists) or restore DISC competency (CDDO, DNA methyltransferase and HDAC inhibitors); reduce pro-survival Bcl2 homologues (Oblimersen sodium [AS-Bcl2], AS-Mcl1) or deliver a pro-apoptotic BH3 protein burden (BH3 peptides, gossypol, ABT737); or repress IAPs (Smac/Diablo peptides, AS-XIAP, AS-Survivin). As our knowledge of apoptosis dysregulation in neuroblastoma evolves, the possibilities for pro-apoptotic therapeutics seems not only promising, but a realistic adjunct to conventional treatments.
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http://dx.doi.org/10.1016/j.canlet.2005.01.048DOI Listing
October 2005