Publications by authors named "Mark W Kieran"

195 Publications

A global approach to long-term follow-up of targeted and immune-based therapy in childhood and adolescence.

Pediatr Blood Cancer 2021 Apr 16:e29047. Epub 2021 Apr 16.

ACCELERATE Platform LTFU Working Group Co-Chair, ACCELERATE, Brussels, Belgium.

While considerable efforts and progress in our understanding of the long-term toxicities of surgery, radiation and chemotherapy in children with cancer have been made over the last 5 decades, there continues to be a wide gap in our knowledge of the long-term health impact of most novel targeted and immunotherapy agents. To address this gap, ACCELERATE, a multi-stakeholder collaboration of clinical and translational academics, regulators from the EMA and FDA, patient/family advocates and members spanning small biotechnology through to large pharmaceutical companies have initiated the development of an international long-term follow-up data registry to collect this important information prospectively. Providing critical safety data on the long-term use of these approved and investigational therapies in children will support the regulatory requirements and labeling information. It will also provide the necessary insight to help guide physicians and families on the appropriateness of a targeted or immune therapy for their child and inform survivorship planning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29047DOI Listing
April 2021

The progeria research foundation 10 international scientific workshop; researching possibilities, ExTENding lives - webinar version scientific summary.

Aging (Albany NY) 2021 03 17;13(6):9143-9151. Epub 2021 Mar 17.

The Progeria Research Foundation, Peabody, MA 01961, USA.

Progeria is an ultra-rare (prevalence 1 in 20 million), fatal, pediatric autosomal dominant premature aging disease caused by a mutation in the gene. This mutation results in accumulation of a high level of an aberrant form of the nuclear membrane protein, Lamin A. This aberrant protein, termed progerin, accumulates in many tissues and is responsible for the diverse array of disease phenotypes. Children die predominantly from premature atherosclerotic cardiovascular disease. The Progeria Research Foundation's 10 International Scientific Workshop took place via webinar on November 2 and 3, 2020. Participants from 30 countries joined in this new, virtual meeting format. Patient family presentations led the program, followed by updates on Progeria's first-ever application for FDA drug approval as well as initial results from the only current Progeria clinical trial. This was followed by presentations of unpublished preclinical data on drugs in development targeting the disease-causing DNA mutation, the aberrant mRNA, progerin protein, and its downstream effector proteins. Tying bench to bedside, clinicians presented new discoveries on the natural history of disease to inform future clinical trial development and new Progeria aortic valve replacement procedures. The program engaged the Progeria research community as a single unit with a common goal - to treat and cure children with Progeria worldwide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.202835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034973PMC
March 2021

Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1).

Acta Neuropathol 2021 04 14;141(4):605-617. Epub 2021 Feb 14.

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.

Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic NF1 inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was FGFR1 mutation, which conferred an additional growth advantage in multiple complementary experimental murine Nf1 models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-021-02276-5DOI Listing
April 2021

Visual outcomes following everolimus targeted therapy for neurofibromatosis type 1-associated optic pathway gliomas in children.

Pediatr Blood Cancer 2021 Apr 18;68(4):e28833. Epub 2020 Dec 18.

Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, Massachusetts.

Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) are limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [three without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in four eyes, and worsened in two eyes; visual and radiologic outcomes were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28833DOI Listing
April 2021

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.

Pediatr Blood Cancer 2021 Feb 2;68(2):e28787. Epub 2020 Nov 2.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, 450 Brookline Avenue, Boston, Massachusetts, 02215, USA.

Background: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG).

Methods: Everolimus was administered at 5 mg/m once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients.

Results: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression.

Conclusion: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28787DOI Listing
February 2021

Resolution of eicosanoid/cytokine storm prevents carcinogen and inflammation-initiated hepatocellular cancer progression.

Proc Natl Acad Sci U S A 2020 09 14;117(35):21576-21587. Epub 2020 Aug 14.

Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B (AFB), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an "eicosanoid and cytokine storm." AFB-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including , , and in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cytokine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2007412117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474612PMC
September 2020

Pediatric cancer research: Surviving COVID-19.

Pediatr Blood Cancer 2020 09 18;67(9):e28435. Epub 2020 Jun 18.

Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, Ohio.

A diverse panel of pediatric cancer advocates and experts, whose collective experience spans the continuum of international academic medicine, industry, government research, and cancer advocacy, recently discussed challenges for pediatric cancer research in the context of coronavirus disease 2019 (COVID-19). Specifically, this special report addresses the following focus areas: (a) the critical role that translational research has played in transforming pediatric cancer outcomes; (b) the current and potential future impact of COVID-19 on pediatric cancer research; (c) target areas of COVID-19 research that may have application in immunity, oncogenesis, and therapeutic discovery; and (d) future considerations and directions in maintaining pediatric cancer research during and after COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323039PMC
September 2020

A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1-associated pediatric low-grade glioma: a Neurofibromatosis Clinical Trials Consortium study.

Neuro Oncol 2020 10;22(10):1527-1535

Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.

Background: Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs.

Methods: Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks.

Results: Twenty-three participants (median age, 9.4 y; range, 3.2-21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants.

Conclusion: Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566451PMC
October 2020

Efficacy and Safety of Dabrafenib in Pediatric Patients with V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study.

Clin Cancer Res 2019 12;25(24):7303-7311

Harvard Medical School, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with V600 mutation-positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients.

Patients And Methods: Patients ages 1 to <18 years who had V600-mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2.

Results: Overall, 32 patients with pLGG were enrolled (part 1, = 15; part 2, = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26-62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64-94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%).

Conclusions: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with V600-mutant pLGG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2177DOI Listing
December 2019

Increasing value of autopsies in patients with brain tumors in the molecular era.

J Neurooncol 2019 Nov 30;145(2):349-355. Epub 2019 Sep 30.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, USA.

Background: Pediatric brain tumors are associated with high morbidity and mortality, in part due to insufficient understanding of tumor biology. With limited tissue allocation for research from surgical specimens, a key barrier to improving biological understanding, brain tumor autopsies have become an increasingly valuable resource. This study reviews the brain tumor autopsy practice at our institution and describes specific emerging research utilization patterns beyond the clinical autopsy report.

Methods: We performed a retrospective analysis of brain tumor autopsies at Boston Children's Hospital (BCH) between 2007 and 2017 and reviewed their consents, neuropathology reports and final diagnoses. We reviewed the method of tissue triaging for research consented autopsies (bioregistry, frozen and fresh tissue) and documented their specific uses.

Results: Ninety-six deaths at BCH were due to brain tumors; 56 autopsies were performed (58.3%), of which 49 (87.5%) were consented for research. Tumor mapping was performed on all cases and tissue was allocated for DNA- and RNA-based sequencing studies (published and ongoing). Three tissue allocations with a postmortem interval of 8 h or less resulted in successful cell lines. Tissue from 14 autopsies was contributed to the National DIPG Registry.

Conclusion: Our institutional pediatric brain tumor autopsy clinical experience demonstrates the increased utility and wide utilization of autopsy-derived tissue for multiple types of research. These results support the increased efforts to obtain research consent for brain tumor autopsy and active collection of unfixed autopsy material in the molecular era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-019-03302-zDOI Listing
November 2019

A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory V600 Mutation-Positive Solid Tumors.

Clin Cancer Res 2019 12 10;25(24):7294-7302. Epub 2019 Sep 10.

The Hospital for Sick Children, University of Toronto, Department of Pediatrics, Toronto, Ontario.

Purpose: The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced V600-mutated cancers.

Patients And Methods: This phase I dose-finding part treated patients ages 1 to <18 years with V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target.

Results: Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily.

Conclusions: In this first clinical trial in pediatric patients with pretreated V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-17-3572DOI Listing
December 2019

Mitogenic and progenitor gene programmes in single pilocytic astrocytoma cells.

Nat Commun 2019 08 19;10(1):3731. Epub 2019 Aug 19.

Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

Pilocytic astrocytoma (PA), the most common childhood brain tumor, is a low-grade glioma with a single driver BRAF rearrangement. Here, we perform scRNAseq in six PAs using methods that enabled detection of the rearrangement. When compared to higher-grade gliomas, a strikingly higher proportion of the PA cancer cells exhibit a differentiated, astrocyte-like phenotype. A smaller proportion of cells exhibit a progenitor-like phenotype with evidence of proliferation. These express a mitogen-activated protein kinase (MAPK) programme that was absent from higher-grade gliomas. Immune cells, especially microglia, comprise 40% of all cells in the PAs and account for differences in bulk expression profiles between tumor locations and subtypes. These data indicate that MAPK signaling is restricted to relatively undifferentiated cancer cells in PA, with implications for investigational therapies directed at this pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11493-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700116PMC
August 2019

Sixty years single institutional experience with pediatric craniopharyngioma: between the past and the future.

Childs Nerv Syst 2020 02 10;36(2):291-296. Epub 2019 Jul 10.

Department of Neurosurgery, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA.

Purpose: To demonstrate the paradigm shift in management strategies of pediatric craniopharyngioma at our institution over the past six decades.

Methods: Retrospective analysis of all pediatric patients with craniopharyngioma treated at Boston Children's Hospital between 1960 and 2017.

Results: One hundred seventy-eight patients with craniopharyngioma were treated between 1960 and 2017; 135 (70 males and 65 females) fulfilled the inclusion criteria. Forty-five patients were treated in the old era (1960-1984) and 90 patients were treated in the new era (1985-2017). Gross total resection (GTR) was achieved in 4% and 43% of patients in old and new eras respectively. Sub-total resection (STR) and radiotherapy (XRT) were performed in 27% and 28% of patients in old and new eras respectively. STR without XRT was performed in 20% and 29% of patients in old and new era respectively. Cyst drainage and adjuvant radiotherapy were performed in 49% of patients in the old era while no patients in the new era underwent such conservative management. Aggressive surgical resection was associated with a higher risk of worsening visual outcomes (20% vs 16%), panhypopituitarism and diabetes insipidus (86% vs 53%), psycho-social impairment (42% vs 26%), and new-onset obesity (33% vs 22%). The mortality rate was higher in the old era in comparison with that of the new one (9% vs 2%).

Conclusion: There was a paradigm shift in management strategies of pediatric craniopharyngioma over the past six decades which in turn affected the long-term outcomes and quality of life of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00381-019-04294-xDOI Listing
February 2020

Outcome of Children Treated for Infantile Hepatic Hemangioendothelioma.

J Pediatr Hematol Oncol 2020 03;42(2):126-130

Departments of Pediatric Hematology and Oncology.

Purpose: Infantile hepatic hemangioendothelioma (IHHE) is the most common hepatic vascular tumor in children. We report on the treatment outcome of our large single-center experience of patients with IHHE over a 9-year period.

Materials And Methods: A retrospective analysis of all IHHE patients treated at the Children Cancer Hospital Egypt from April 2008 through April 2017.

Results: In total, 28 patients (18 females, 10 males) were diagnosed with IHHE with a median age at diagnosis of 3 months. The lesions were multifocal (n=12), focal (n=10), and diffuse (n=6). Six (21.4%) patients initially had low T3 and T4. Eleven patients did not receive any treatment, whereas 1 patient underwent resectional surgery. Sixteen patients received drug treatment, 9 of whom responded well to first-line propranolol/prednisolone, whereas 7 patients needed salvage treatment. Twenty-five patients are alive, whereas 3 patients have died.

Conclusions: Overall, patients with IHHE do well, a significant percentage of whom do not require drug therapy, particularly for those with small focal lesions. In patients with multifocal/diffuse disease, there is a high incidence of low T3 and T4 and while some of these patients did well without additional therapy, those with rapidly progressive lesions during treatment may do poorly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000001536DOI Listing
March 2020

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases.

J Clin Invest 2019 06 17;129(7):2964-2979. Epub 2019 Jun 17.

Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Preoperative stimulation of inflammation resolution via resolvins (RvD2, RvD3, and RvD4) inhibited metastases and induced T cell responses. Ketorolac and resolvins exhibited synergistic antitumor activity and prevented surgery- or chemotherapy-induced dormancy escape. Thus, simultaneously blocking the ensuing proinflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI127282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597207PMC
June 2019

Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.

Nat Commun 2019 06 3;10(1):2400. Epub 2019 Jun 3.

Department of Pathology, Brigham and Women's Hospital, Boston, USA.

BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-10307-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546744PMC
June 2019

Hedgehog signaling inhibitors in solid and hematological cancers.

Cancer Treat Rev 2019 Jun 6;76:41-50. Epub 2019 May 6.

Ameriderm Research, 725 W Granada Blvd Ste 44, Ormond Beach, FL 32174, USA; University of Central Florida, Orlando, FL, USA. Electronic address:

Background: The hedgehog signaling pathway is normally tightly regulated. Mutations in hedgehog pathway components may lead to abnormal activation. Aberrantly activated hedgehog signaling plays a major role in the development of solid and hematological cancer. In recent years, inhibitors have been developed that attenuate hedgehog signaling; 2 have been approved for use in basal cell carcinoma (BCC), while others are under development or in clinical trials. The aim of this review is to provide an overview of known hedgehog inhibitors (HHIs) and their potential for the treatment of hematological cancers and solid tumors beyond BCC.

Design: Published literature was searched to identify articles relating to HHIs in noncutaneous cancer. Both preclinical and clinical research articles were included. In addition, relevant clinical trial results were identified from www.clinicaltrials.gov. Information on the pharmacology of HHIs is also included.

Results: HHIs show activity in a variety of solid and hematological cancers. In preclinical studies, HHIs demonstrated efficacy in pancreatic cancer, rhabdomyosarcoma, breast cancer, and acute myeloid leukemia (AML). In clinical studies, HHIs showed activity in medulloblastoma, as well as prostate, pancreatic, and hematological cancers. Current clinical trials testing the efficacy of HHIs are underway for prostate, pancreatic, and breast cancers, as well as multiple myeloma and AML.

Conclusions: As clinical trial results become available, it will be possible to discern which additional tumor types are suited to HHI mono- or combination therapy with other anticancer agents. The latter strategy may be useful for delaying or overcoming drug resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctrv.2019.04.005DOI Listing
June 2019

Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma.

Neuro Oncol 2019 03;21(4):537-546

Division of Hematology/Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago and Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors.

Methods: This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir.

Results: Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection.

Conclusions: GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation.

Clinical Trial Registry: ClinicalTrials.gov NCT00634231.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noy202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422437PMC
March 2019

Aspirin-triggered proresolving mediators stimulate resolution in cancer.

Proc Natl Acad Sci U S A 2019 03 12;116(13):6292-6297. Epub 2019 Mar 12.

Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1804000116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442621PMC
March 2019

Cutaneous reactions to targeted therapies in children with CNS tumors: A cross-sectional study.

Pediatr Blood Cancer 2019 06 28;66(6):e27682. Epub 2019 Feb 28.

Dermatology Program, Boston Children's Hospital, Boston, Massachusetts.

Background: MAPK (RAS-RAF-MEK-ERK-MAP) and mTOR inhibitors are novel treatments for pediatric central nervous system (CNS) tumors. The literature on common cutaneous adverse reactions to these therapies is sparse in the pediatric population. The aim of this study was to describe common cutaneous adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors.

Methods: In this cross-sectional study, patients younger than 21 years of age receiving BRAF, MEK, and mTOR inhibitor monotherapy for a CNS tumor were enrolled over a one-year period. Full body skin examination, photographs of dermatologic findings, and initial treatment recommendations were included at the initial visit, and follow-up skin examinations were recommended every three months.

Results: Twenty-two patients were enrolled in the study. Fifty percent (11/22) received trametinib, a MEK inhibitor, 27.3% (6/22) received dabrafenib, a BRAF inhibitor, and 22.7% (5/22) received everolimus, an mTOR inhibitor. Median age at visit was 11 years (range, 3-19). Median time from treatment initiation to skin examination was 4.5 months (range, 0-43). Ninety-six percent (21/22) of all patients had at least one skin reaction. The most common reactions across treatment groups included follicular/acneiform eruptions and xerosis. Two patients on MEK inhibitors and one patient on a BRAF inhibitor required therapy cessation due to severe cutaneous reactions.

Conclusions: Cutaneous reactions to targeted anticancer therapy in children are common, treatable, and rarely require drug dose reduction or discontinuation. Routine surveillance and early intervention may improve quality of life and facilitate continuation of life-saving therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27682DOI Listing
June 2019

Challenges to curing primary brain tumours.

Nat Rev Clin Oncol 2019 08;16(8):509-520

CRUK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.

Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic and microenvironmental properties of neural tissues. In an attempt to encourage progress in our understanding and ability to successfully treat patients with brain tumours, Cancer Research UK convened an international panel of clinicians and laboratory-based scientists to identify challenges that must be overcome if we are to cure all patients with a brain tumour. The seven key challenges summarized in this Position Paper are intended to serve as foci for future research and investment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41571-019-0177-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650350PMC
August 2019

Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor.

Proc Natl Acad Sci U S A 2019 01 15;116(5):1698-1703. Epub 2019 Jan 15.

Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum- and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived "surge" of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1803999116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358686PMC
January 2019

Tumor dissemination through surgical tracts in diffuse intrinsic pontine glioma.

J Neurosurg Pediatr 2018 Dec;22(6):678-683

3Department of Pediatric Hematology and Oncology.

OBJECTIVEDiffuse intrinsic pontine glioma (DIPG) is a highly aggressive and lethal brainstem tumor in children. In the 1980s, routine biopsy at presentation was abandoned since it was claimed "unnecessary" for diagnosis. In the last decade, however, several groups have reincorporated this procedure as standard of care or in the context of clinical trials. Expert neurosurgical teams report no mortality and acceptable morbidity, and no relevant complications have been previously described. The aim of this study was to review needle tract dissemination as a potential complication in DIPG.METHODSThe authors retrospectively analyzed the incidence of dissemination through surgical tracts in DIPG patients who underwent biopsy procedures at diagnosis in 3 dedicated centers. Clinical records and images as well as radiation dosimetry from diagnosis to relapse were reviewed.RESULTSFour patients (2 boys and 2 girls, age range 6-12 years) had surgical tract dissemination: in 3 cases in the needle tract and in 1 case in the Ommaya catheter tract. The median time from biopsy to identification of dissemination was 5 months (range 4-6 months). The median overall survival was 11 months (range 7-12 months). Disseminated lesions were in the marginal radiotherapy field (n = 2), out of the field (n = 1), and in the radiotherapy field (n = 1).CONCLUSIONSAlthough surgical tract dissemination in DIPG is a rare complication (associated with 2.4% of procedures in this study), it should be mentioned to patients and family when procedures involving a surgical tract are proposed. The inclusion of the needle tract in the radiotherapy field may have only limited benefit. Future studies are warranted to explore the benefit of larger radiotherapy fields in patients with DIPG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2018.6.PEDS17658DOI Listing
December 2018

Chemotherapy-generated cell debris stimulates colon carcinoma tumor growth via osteopontin.

FASEB J 2019 01 29;33(1):114-125. Epub 2018 Jun 29.

Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Colon cancer recurrence after therapy, such as 5-fluorouracil (5-FU), remains a challenge in the clinical setting. Chemotherapy reduces tumor burden by inducing cell death; however, the resulting dead tumor cells, or debris, may paradoxically stimulate angiogenesis, inflammation, and tumor growth. Here, we demonstrate that 5-FU-generated colon carcinoma debris stimulates the growth of a subthreshold inoculum of living tumor cells in subcutaneous and orthotopic models. Debris triggered the release of osteopontin (OPN) by tumor cells and host macrophages. Both coinjection of debris and systemic treatment with 5-FU increased plasma OPN levels in tumor-bearing mice. RNA expression levels of secreted phosphoprotein 1, the gene that encodes OPN, correlate with poor prognosis in patients with colorectal cancer and are elevated in chemotherapy-treated patients who experience tumor recurrence vs. no recurrence. Pharmacologic and genetic ablation of OPN inhibited debris-stimulated tumor growth. Systemic treatment with a combination of a neutralizing OPN antibody and 5-FU dramatically inhibited tumor growth. These results demonstrate a novel mechanism of tumor progression mediated by OPN released in response to chemotherapy-generated tumor cell debris. Neutralization of debris-stimulated OPN represents a potential therapeutic strategy to overcome the inherent limitation of cytotoxic therapies as a result of the generation of cell debris.-Chang, J., Bhasin, S. S., Bielenberg, D. R., Sukhatme, V. P., Bhasin, M., Huang, S., Kieran, M. W., Panigrahy, D. Chemotherapy-generated cell debris stimulates colon carcinoma tumor growth via osteopontin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201800019RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355061PMC
January 2019

The Integration of Biology Into the Treatment of Diffuse Intrinsic Pontine Glioma: A Review of the North American Clinical Trial Perspective.

Front Oncol 2018 18;8:169. Epub 2018 May 18.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.

Dramatic advances in the molecular analysis of diffuse intrinsic pontine glioma have occurred over the last decade and resulted in the identification of potential therapeutic targets. In spite of these advances, no significant improvement in the outcome has been achieved and median survival remains approximately 10 months. An understanding of the approaches that have been taken to date, why they failed, and how that information can lead the field forward is critical if we are to change the . In this review, we will discuss the clinical trial landscape in North America with an overview of historical approaches that failed and what might account for this failure. We will then provide a discussion of how our understanding of the genotype of this disease has led to the development of a number of trials targeting the mutations and epigenome of diffuse intrinsic pontine gliomas and the issues related to these trials. Similarly, the introduction of methodologies to address penetration across the blood-brain barrier will be considered in the context of both targeted approaches, epigenetic modification, and immune surveillance of these tumors. The comprehensive analysis of these data, generated through cooperative groups, collaborative clinical trials, and pilot studies in North America will be the focus of the IVth Memorial Alicia Pueyo international symposium in Barcelona on March 12th, 2018 and will be compared and contrasted with a similar comprehensive analysis of the European data with the goal of bringing all of these data together to develop a uniform platform on which new rational trials can be based.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2018.00169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968382PMC
May 2018

Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries.

J Clin Oncol 2018 07 10;36(19):1963-1972. Epub 2018 May 10.

Lindsey M. Hoffman and Nicholas K. Foreman, University of Colorado Denver; Lindsey M. Hoffman and Nicholas K. Foreman, Children's Hospital Colorado, Aurora, CO; Sophie E.M. Veldhuijzen van Zanten, Esther Hulleman, Gertjan J.L. Kaspers, Esther Sanchez, and Dannis G. van Vuurden, Vrije Universiteit University Medical Center, Amsterdam; William P. Vandertop, Academy of Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Niclas Colditz, Marion Hoffmann, Brigitte Bison, Monika Warmuth-Metz, and Christof M. Kramm, University Medical Center Goettingen, Goettingen; Torsten Pietsch and Gerrit H. Gielen, University of Bonn Medical Center, Bonn; David T.W. Jones, Dominik Sturm, Stefan M. Pfister, and Elke Pfaff, German Cancer Research Center, Hopp-Children's Cancer Center at the Nationale Centrum für Tumorerkrankungen Heidelberg, and German Consortium for Translational Cancer Research; Dominik Sturm, Stefan M. Pfister, and Elke Pfaff, Heidelberg University Hospital, Heidelberg, Germany; Joshua Baugh, Brooklyn Chaney, Adam Lane, Christine Fuller, Nancy Yanez Escorza, Renee Doughman, Rachid Drissi, James Leach, Blaise Jones, and Maryam Fouladi, Cincinnati Children's Hospital Medical Center, Cincinnati; Emmett Broxson, Wright State University and The Children's Medical Center, Dayton, OH; Lili Miles, Nemours Children's Hospital, Orlando, FL; Cynthia Hawkins, Ute Bartels, and Eric Bouffet, The Hospital for Sick Children, Toronto, Ontario; Anne Sophie Carret, Centre Hospitalier Universitaire Sainte-Justine; Nada Jabado, McGill University, Montreal, Quebec, Canada; Stewart Goldman, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL; Sarah Leary, Seattle Children's Hospital, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA; Roger Packer, Children's National Health System; Javad Nazarian, Children's National Medical Center, Washington, DC; Katherine E. Warren, National Cancer Institute, Bethesda, MD; Alberto Broniscer, St Jude Children's Research Hospital, Memphis, TN; Mark W. Kieran, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA; Jane Minturn, Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Melanie Comito, The Pennsylvania State University, Hershey, PA; Chie-Schin Shih, Indiana University, Indianapolis, IN; Soumen Khatua, The University of Texas MD Anderson Cancer Center; Murali Chintagumpala, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX; Timothy Hassall, Lady Cilento Children's Hospital, Brisbane, Queensland; David S. Ziegler, Kids Cancer Centre, Sydney Children's Hospital, Randwick; David S. Ziegler, University of New South Wales, Sydney, New South Wales; Nicholas Gottardo and Hetal Dholaria, Princess Margaret Hospital for Children, Perth, Western Australia, Australia; Martin Benesch, Medical University of Graz, Graz, Austria; Nathalie Boddaert. Stephanie Puget, and Raphaël Calmon, Hôpital Necker Enfants Malades; Pascale Varlet, Hôpital Sainte-Anne, Université Paris V Descartes, Sorbonne Paris Cité, Paris; Géraldine Giraud, David Castel, and Jacques Grill, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif, France; Géraldine Giraud, Uppsala University, Uppsala, Sweden; Chris Jones, The Institute of Cancer Research, Sutton; Darren Hargrave, Great Ormond Street Hospital, London; Guirish A. Solanki, Birmingham Women's and Children's Hospital, Birmingham; Simon Bailey, Great North Children's Hospital, Victoria Wing, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; Piergiorgio Modena and Marzia Giagnacovo, Sant' Anna Como General Hospital, Como; Manila Antonelli, Sapienza University of Rome, Rome; Veronica Biassoni and Maura Massimino, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Nicolas U. Gerber and Michael A. Grotzer, University Children's Hospital of Zurich, Zurich; André O. von Bueren, University Hospital of Geneva and University of Geneva, Geneva, Switzerland; and Filip Jadrijevic Cvrlje and Gertjan J.L. Kaspers, Children's Hospital Zagreb, Zagreb, Croatia.

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2017.75.9308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075859PMC
July 2018

Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma.

Neuro Oncol 2018 10;20(11):1547-1555

Children's Healthcare of Atlanta & Emory University, Atlanta, Georgia.

Background: Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets.

Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment.

Results: Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%-97%).

Conclusions: Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noy070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176802PMC
October 2018

Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome.

JAMA 2018 04;319(16):1687-1695

Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.

Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment.

Objective: To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS.

Design, Setting, And Participants: Cohort study comparing contemporaneous (birth date ≥1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression. Treatment cohorts included patients from 2 single-group, single-site clinical trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated patients originated from a separate natural history study (n = 103). The cutoff date for patient follow-up was January 1, 2018.

Exposure: Treated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications.

Main Outcomes And Measures: The primary outcome was mortality. The primary analysis compared treated patients from the first lonafarnib trial with matched untreated patients. A secondary analysis compared the combined cohorts from both lonafarnib trials with matched untreated patients.

Results: Among untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04).

Conclusions And Relevance: Among patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow-up. Study interpretation is limited by its observational design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2018.3264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933395PMC
April 2018

Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq.

Science 2018 04;360(6386):331-335

Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aao4750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949869PMC
April 2018