Publications by authors named "Andrew S Brohl"

48 Publications

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

Cell Rep 2021 Nov;37(8):110047

University of Toronto Musculoskeletal Oncology Unit, Sinai Health System; Department of Surgery, University of Toronto, Toronto, ON, Canada.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.110047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642810PMC
November 2021

A Case of Retroperitoneal Synovial Sarcoma in Pregnancy Treated with Antepartum Doxorubicin plus Ifosfamide Chemotherapy.

Case Rep Oncol Med 2021 16;2021:9982171. Epub 2021 Jul 16.

Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

We report a case of a 25-year-old pregnant woman diagnosed with a large, unresectable retroperitoneal synovial sarcoma. Successful neoadjuvant treatment with doxorubicin plus ifosfamide prepartum and continuing postpartum resulted in significant disease response allowing for later tumor resection. Following the first prepartum chemotherapy cycle, a decreased amniotic fluid index was noted, representing a potential complication of chemotherapy. Induction of labor was performed at 33 weeks gestation with excellent outcome in the newborn. This case highlights the complex medical decision-making process in the setting of cancer diagnosed during pregnancy, balancing oncologic and obstetric concerns, and to our knowledge is only the second reported case of synovial sarcoma treated with neoadjuvant cytotoxic chemotherapy in the antepartum period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/9982171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313357PMC
July 2021

First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): primary and biomarker analyses of a phase II study.

J Immunother Cancer 2021 07;9(7)

Division of Dermatology, University of Washington Medical Center at South Lake Union, Seattle, Washington, USA.

Background: Avelumab (anti-programmed death ligand 1 (PD-L1)) is approved in multiple countries for the treatment of metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer. We report efficacy and safety data and exploratory biomarker analyses from a cohort of patients with mMCC treated with first-line avelumab in a phase II trial.

Methods: Patients with treatment-naive mMCC received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was durable response, defined as objective response (complete or partial response; assessed by independent review) lasting ≥6 months. Additional assessments included progression-free survival (PFS), overall survival (OS), safety, and biomarker analyses.

Results: In 116 patients treated with avelumab, median follow-up was 21.2 months (range: 14.9-36.6). Thirty-five patients had a response lasting ≥6 months, giving a durable response rate of 30.2% (95% CI: 22.0% to 39.4%). The objective response rate was 39.7% (95% CI: 30.7% to 49.2%). Median PFS was 4.1 months (95% CI: 1.4 to 6.1) and median OS was 20.3 months (95% CI: 12.4 to not estimable). Response rates were numerically higher in patients with PD-L1+ tumors, Merkel cell polyomavirus (MCPyV)-negative tumors, and tumors with increased intratumoral CD8 T-cell density. Exploratory analyses did not identify a biomarker that could reliably predict a response to first-line treatment with avelumab; however, a novel gene expression signature to identify the presence of MCPyV+ tumors was derived. Treatment-related adverse events (any grade) occurred in 94 (81.0%) patients, including grade 3/4 events in 21 (18.1%) patients; no treatment-related deaths occurred.

Conclusion: In patients with mMCC, first-line treatment with avelumab led to responses in 40% and durable responses in 30%, and was associated with a low rate of grade 3/4 treatment-related adverse events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2021-002646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311489PMC
July 2021

An analysis of the use of targeted therapies in patients with advanced Merkel cell carcinoma and an evaluation of genomic correlates of response.

Cancer Med 2021 Sep 16;10(17):5889-5896. Epub 2021 Jul 16.

Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Background: The use of targeted therapy remains a treatment consideration for some patients with advanced Merkel cell carcinoma (MCC). However, supportive data on the use of targeted therapy approaches are limited. Thus, we sought to evaluate the responsiveness of targeted agents in patients with advanced MCC.

Methods: An institutional MCC database identified patients who were treated with targeted therapy. For the purpose of this study, targeted therapy was defined as any multi-targeted tyrosine kinase inhibitor or inhibitor of the PI3K-pathway. Clinical benefit was defined as complete response, partial response, or stable disease (SD) ≥6 months. A subset of patient samples underwent next-generation sequencing (NGS), Merkel cell polyomavirus testing, and PD-L1/PD-1 expression testing.

Results: Nineteen patients with MCC treated with targeted therapy were identified, 21 targeted therapy regimens were evaluable for response in 18 patients. Four of twenty-one (19%) of evaluable regimens were associated with clinical benefit with the best overall response of SD. The durations of SD were 13.6 months (59 weeks), 9.7 months (42 weeks), 7.6 months (33 weeks), and 7.2 months (31 weeks). Of the four patients who derived clinical benefit, three were treated with pazopanib alone and one was treated with pazopanib plus everolimus. No difference in the rate of clinical benefit between molecular disease subtypes was detected nor was associated with any specific genomic alteration.

Conclusion: In our series, targeted agents elicited a disease control rate of 19% in patients with advanced MCC, with a best overall response of SD. Pazopanib alone or in combination exhibited a rate of disease control of 36% (4 of 11 with SD ≥6 months).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.4138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419775PMC
September 2021

Mutant p53s and chromosome 19 microRNA cluster overexpression regulate cancer testis antigen expression and cellular transformation in hepatocellular carcinoma.

Sci Rep 2021 06 16;11(1):12673. Epub 2021 Jun 16.

Sarcoma Department, H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.

A subset of hepatocellular carcinoma (HCC) overexpresses the chromosome 19 miRNA cluster (C19MC) and is associated with an undifferentiated phenotype marked by overexpression of cancer testis antigens (CTAs) including anti-apoptotic melanoma-A antigens (MAGEAs). However, the regulation of C19MC miRNA and MAGEA expression in HCCs are not understood. Here we show that, C19MC overexpression is tightly linked to a sub-set of HCCs with transcription-incompetent p53. Using next-generation and Sanger sequencing we found that, p53 in Hep3B cells is impaired by TP53-FXR2 fusion, and that overexpression of the C19MC miRNA-520G in Hep3B cells promotes the expression of MAGEA-3, 6 and 12 mRNAs. Furthermore, overexpression of p53-R175H and p53-R273H mutants promote miR-520G and MAGEA RNA expression and cellular transformation. Moreover, IFN-γ co-operates with miR-520G to promote MAGEA expression. On the other hand, metals such as nickel and zinc promote miR-526B but not miR-520G, to result in the suppression of MAGEA mRNA expression, and evoke cell death through mitochondrial membrane depolarization. Therefore our study demonstrates that a MAGEA-promoting network involving miR-520G, p53-defects and IFN-γ that govern cellular transformation and cell survival pathways, but MAGEA expression and survival are counteracted by nickel and zinc combination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-91924-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209049PMC
June 2021

Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma.

J Immunother Cancer 2021 04;9(4)

Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center, Baltimore, Maryland, USA.

Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017.

Methods: In this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months.

Results: Overall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies.

Conclusions: This study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority.

Trial Registration Number: NCT02267603.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2021-002478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061836PMC
April 2021

Circulating Tumor Cells and Biomarker Modulation with Olaratumab Monotherapy Followed by Olaratumab plus Doxorubicin: Phase Ib Study in Patients with Soft-Tissue Sarcoma.

Mol Cancer Ther 2021 01 11;20(1):132-141. Epub 2020 Nov 11.

Royal Marsden Hospital/Institute of Cancer Research, London, United Kingdom.

This phase Ib study enumerated whole blood circulating tumor cells (CTC) and evaluated biomarkers in patients with potentially resectable soft-tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for one cycle followed by up to six cycles of olaratumab (20 mg/kg, cycles 1-2; 15 mg/kg, cycles 3-7) plus doxorubicin (75 mg/m on day 1). CTCs, platelet-derived growth factor receptors (PDGFR), and PDGF ligand expression in tumor tissue pre- and post-olaratumab monotherapy were evaluated. Antitumor activity, safety, pharmacokinetics, and PET/biomarker association with clinical outcome were assessed. Of 51 treated patients, 35, 43, and 37 were evaluable for CTC enumeration, PDGFRs, and PDGF ligand expression, respectively. An increase in CTCs at cycle 1 day 8 was observed, followed by a significant reduction by cycle 3 day 1 or 30-day follow-up. Decrease in CTC counts after olaratumab monotherapy was higher in patients with disease control than without disease control (57.9% vs. 31.2%). Baseline IHC expression was positive in most patients for PDGFRα [ = 31 (72.1%)] and PDGFRβ [ = 36 (83.7%)]. Similar rates were observed post-olaratumab monotherapy [PDGFRα, = 30 (69.8%); PDGFRβ, = 33 (76.7%)]. Eleven patients (29.7%) showed a 30% reduction by RT-PCR in PDGFRα at cycle 2. PDGFR expression and PET response showed no correlation with clinical outcome. Safety and pharmacokinetic profiles were consistent with previous reports. This study, the first to use a validated method for CTC detection, confirms that CTC enumeration in STS is feasible. However, no correlation was observed between PDGFRα expression and clinical outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-20-0441DOI Listing
January 2021

Health-related quality of life trajectory of treatment-naive patients with Merkel cell carcinoma receiving avelumab.

Future Oncol 2020 Sep 17;16(27):2089-2099. Epub 2020 Sep 17.

Department of Medicine, Weill Cornell Medical College & Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

To evaluate changes in health-related quality of life (HRQoL) in a Phase II trial (NCT02155647) of treatment-naive patients with metastatic Merkel cell carcinoma treated with avelumab (15-month follow-up). Mixed-effect Models for Repeated Measures were applied to HRQoL data (FACT-M; EQ-5D-5L) to assess changes over time. Clinically derived progression-free survival was compared with HRQoL deterioration-free survival. Overall, we saw relative stability in HRQoL among 116 included patients, with nonprogression associated with statistically and clinically meaningful better HRQoL compared with progressive disease. Deterioration-free survival rates (49-72% at 6 months, 40-58% at 12 months) were consistently higher/better compared with progression-free survival rates (41/31% at 6/12 months). These findings show unique longitudinal HRQoL data for treatment-naive metastatic Merkel cell carcinoma patients treated with avelumab. : NCT02155647 (ClinicalTrials.gov).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0426DOI Listing
September 2020

Regulation of MYO18B mRNA by a network of C19MC miRNA-520G, IFN-γ, CEBPB, p53 and bFGF in hepatocellular carcinoma.

Sci Rep 2020 07 23;10(1):12371. Epub 2020 Jul 23.

Sarcoma Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.

MYO18B has been proposed to contribute to the progression of hepatocellular carcinoma (HCC). However, the signals that govern MYO18B transcription are not known. Here we show that, a network of C19MC miRNA-520G, IFN-γ, CEBPB and p53 transcriptional-defects promote MYO18B mRNA expression in HCCs. IFN-γ by itself suppresses MYO18B transcription, but promotes it when miRNA-520G is stably overexpressed. Similarly, CEBPB-liver-enriched activator protein (LAP) isoform overexpression suppresses MYO18B transcription but promotes transcription when the cells are treated with IFN-γ. Furthermore, miR-520G together with mutant-p53 promotes MYO18B transcription. Conversely, bFGF suppresses MYO18B mRNA irrespective of CEBPB, miR-520G overexpression or IFN-γ treatment. Finally high MYO18B expression reflects poor prognosis while high MYL5 or MYO1B expression reflects better survival of HCC patients. Thus, we identified a network of positive and negative regulators of MYO18B mRNA expression which reflects the survival of HCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-69179-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378193PMC
July 2020

congenital predisposition to Wilms' tumor: novel mutations and presentation in a sibling pair.

Cold Spring Harb Mol Case Stud 2020 08 25;6(4). Epub 2020 Aug 25.

Adolescent and Young Adult Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.

Wilms' tumor is the most common renal malignancy in children. In addition to staging, molecular risk stratification, such as loss of heterozygosity (LOH) in Chromosomes 1 and 16, is being increasingly used. Although genetic predisposition syndromes have been well-characterized in some Wilms' tumors, recent sequencing and biology efforts are expanding the classification of this malignancy. Here we present a case of siblings with remarkably similar presentations of bilateral Wilms' tumor at ∼12 mo of age. Thorough exam after the younger sibling was diagnosed did not reveal any signs to suggest one of the known Wilms' predisposition syndromes. Both were treated with standard therapies with good response and long-term sustained complete remission of 53 and 97 mo, respectively. Whole-exome sequencing was performed on a tumor sample from each patient and matched blood from one, revealing a shared truncation mutation of in all three samples with heterozygosity in the germline sample. loss has been recently implicated in early-stage Wilms' tumors with epithelioid morphology. These siblings expand the phenotype for presentation with multifocal disease with retained excellent response to standard therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a004796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476416PMC
August 2020

Chemotherapy improves distant control in localized high-grade soft tissue sarcoma of the extremity/trunk.

Clin Sarcoma Res 2020 9;10:11. Epub 2020 Jul 9.

Department of Sarcoma, Moffitt Cancer Center and Research Institute, Tampa, FL USA.

Background: Soft tissue sarcomas (STS) are rare and heterogeneous tumors making chemotherapy use controversial. Our goal was to identify a subset of patients with primary STS that benefit with the addition of chemotherapy.

Methods: A retrospective chart review included intermediate to high-grade localized primary STS of the extremity/trunk, and tumor size > 5 cm. The effect of chemotherapy was evaluated for local control (LC), distant control (DC), progression free survival (PFS), and overall survival (OS).

Results: In this cohort (n = 273), patients were treated with surgery (98%), radiation (81%), and chemotherapy (24.5%). With a median follow-up of 51 months, the entire cohort's 5-year LC, DC, PFS, and OS are 79.1%, 59.9%, 43.8%, and 68.7%, respectively. The addition of chemotherapy did not provide a DC benefit (p = 0.238) for the entire cohort. High-grade disease (n = 210) experienced a 5-year benefit in DC (68% vs. 54.4%, p = 0.04), which was more pronounced with MAI (Mesna, Adriamycin, Ifosfamide) based regimens (74.2%, p = 0.016), and a 5-year PFS (50.8% vs 45%, p = 0.025) and OS benefit (76.2% vs 70%, p = 0.067) vs. no chemotherapy. On multivariate analysis of the high-grade subset, chemotherapy independently predicted for a DC benefit (HR 0.48 95% CI 0.26-89, p = 0.019). The benefit of chemotherapy was more pronounced with MAI, showing a significant benefit in DC (HR 0.333 95% CI 0.145-0.767, p = 0.01) and PFS (HR 0.52 95% CI 0.28-0.99, p = 0.047).

Conclusion: In patients with localized STS > 5 cm, the high-grade subset had a distant control benefit with the addition of chemotherapy, leading to improved progression free survival. This is more pronounced with the use of MAI and should be considered in patients eligible for this regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13569-020-00132-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350709PMC
July 2020

Neoadjuvant Checkpoint Inhibitor Therapy for Merkel Cell Carcinoma.

J Clin Oncol 2020 08 12;38(22):2471-2475. Epub 2020 Jun 12.

Department of Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL.

A 78-year-old man presented with rapidly enlarging lymph nodes in the right preauricular region and neck. Needle biopsy revealed a cytokeratin 20-positive, high-grade neuroendocrine neoplasm consistent with Merkel cell carcinoma (MCC). Cross-sectional imaging disclosed a 5.2-cm intraparotid mass and extensive adenopathy in the ipsilateral cervical and submental chains (Figs 1A and 1C), without distant metastatic disease. A skin examination did not reveal a primary lesion (hence, stage IIIA, T0N1bM0). The patient's history was notable for hypertension, diet-controlled diabetes type II, high cholesterol, and a past history of numerous cutaneous basal and squamous cell carcinomas. He was quite active but reported discomfort from the bulk of the tumors. The patient was evaluated by the surgical oncology team, who believed that the parotid mass and cervical adenopathy were technically resectable but that resection carried a substantial risk of morbidity because of the potential need to sacrifice the facial and/or spinal accessory nerves and because of a likely margin-positive (R1 or R2) result. He was referred to the medical oncology team to discuss management options for regionally advanced, "borderline-resectable" MCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00752DOI Listing
August 2020

Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial.

J Immunother Cancer 2020 05;8(1)

Division of Dermatology, Department of Medicine, University of Washington Medical Center at South Lake Union, Seattle, Washington, USA.

Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with a high risk of metastasis. In 2017, avelumab (anti-programmed death-ligand 1 (PD-L1)) became the first approved treatment for patients with metastatic MCC (mMCC), based on the occurrence of durable responses in a subset of patients. Here, we report long-term efficacy and safety data and exploratory biomarker analyses in patients with mMCC treated with avelumab.

Methods: In a cohort of this single-arm, phase 2 trial (JAVELIN Merkel 200), patients with mMCC and disease progression after prior chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate (ORR) by independent review per Response Evaluation Criteria in Solid Tumors V.1.1. Other assessments included duration of response, progression-free survival, overall survival (OS), safety and biomarker analyses.

Results: As of 14 September 2018, 88 patients had been followed up for a median of 40.8 months (range 36.4-49.7 months). The ORR was 33.0% (95% CI 23.3% to 43.8%), including a complete response in 11.4% (10 patients), and the median duration of response was 40.5 months (95% CI 18.0 months to not estimable). As of 2 May 2019 (≥44 months of follow-up), the median OS was 12.6 months (95% CI 7.5 to 17.1 months) and the 42-month OS rate was 31% (95% CI 22% to 41%). Of long-term survivors (OS >36 months) evaluable for PD-L1 expression status (n=22), 81.8% had PD-L1+ tumors. In exploratory biomarker analyses, high tumor mutational burden (≥2 non-synonymous somatic variants per megabase) and high major histocompatibility complex class I expression (30% of tumors with highest expression) were associated with trends for improved ORR and OS. In long-term safety assessments (≥36 months of follow-up), no new or unexpected adverse events were reported, and no treatment-related deaths occurred.

Conclusions: Avelumab showed continued durable responses and meaningful long-term survival outcomes in patients with mMCC, reinforcing avelumab as a standard-of-care treatment option for this disease.

Trial Registration Number: NCT02155647.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-000674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239697PMC
May 2020

The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss.

PLoS Genet 2020 04 20;16(4):e1008642. Epub 2020 Apr 20.

Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center, Florida, United States of America.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy. Though the molecular underpinnings of this cancer have been largely unexplored, recurrent chromosomal breakpoints affecting a noncoding region on chr19q13, which includes the chromosome 19 microRNA cluster (C19MC), have been reported in several cases. We performed comprehensive molecular profiling on samples from 14 patients diagnosed with UESL. Congruent with prior reports, we identified structural variants in chr19q13 in 10 of 13 evaluable tumors. From whole transcriptome sequencing, we observed striking expressional activity of the entire C19MC region. Concordantly, in 7 of 7 samples undergoing miRNAseq, we observed hyperexpression of the miRNAs within this cluster to levels >100 fold compared to matched normal tissue or a non-C19MC amplified cancer cell line. Concurrent TP53 mutation or copy number loss was identified in all evaluable tumors with evidence of C19MC overexpression. We find that C19MC miRNAs exhibit significant negative correlation to TP53 regulatory miRNAs and K-Ras regulatory miRNAs. Using RNA-seq we identified that pathways relevant to cellular differentiation as well as mRNA translation machinery are transcriptionally enriched in UESL. In summary, utilizing a combination of next-generation sequencing and high-density arrays we identify the combination of C19MC hyperexpression via chromosomal structural event with TP53 mutation or loss as highly recurrent genomic features of UESL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1008642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192511PMC
April 2020

The genetic script of metastasis.

Biol Rev Camb Philos Soc 2019 Oct 30. Epub 2019 Oct 30.

Sarcoma Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, U.S.A.

Metastasis is a pivotal event that changes the course of cancers from benign and treatable to malignant and difficult to treat, resulting in the demise of patients. Understanding the genetic control of metastasis is thus crucial to develop efficient and sustainable targeted therapies. Here we discuss the alterations in epigenetic mechanisms, transcription, chromosomal instability, chromosome imprinting, non-coding RNAs, coding RNAs, mutant RNAs, enhancers, G-quadruplexes, and copy number variation to dissect the genetic control of metastasis. We conclude that the genetic control of metastasis is predominantly executed through epithelial to mesenchymal transition and evasion of cell death. We discuss how genetic regulatory mechanisms can be harnessed for therapeutic purposes to achieve sustainable control over cancer metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/brv.12562DOI Listing
October 2019

Small molecule inhibition of lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) alone and in combination in Ewing sarcoma cell lines.

PLoS One 2019 24;14(9):e0222228. Epub 2019 Sep 24.

Sunshine Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.

Ewing Sarcoma (ES) is characterized by recurrent translocations between EWSR1 and members of the ETS family of transcription factors. The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While inhibitors of both histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1) subunits of the NuRD complex demonstrate single agent activity in preclinical models, combination strategies have not been investigated. We selected 7 clinically utilized chemotherapy agents, or active metabolites thereof, for experimentation: doxorubicin, cyclophosphamide, vincristine, etoposide and irinotecan as well as the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509. All agents were tested at clinically achievable concentrations in 4 ES cell lines. All possible 2 drug combinations were then tested for potential synergy. Order of addition of second-line conventional combination therapy agents was tested with the addition of SP2509. In two drug experiments, synergy was observed with several combinations, including when SP2509 was paired with topoisomerase inhibitors or romidepsin. Addition of SP2509 after treatment with second-line combination therapy agents enhanced treatment effect. Our findings suggest promising combination treatment strategies that utilize epigenetic agents in ES.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759167PMC
March 2020

The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy.

Clin Cancer Res 2019 10 9;25(19):5961-5971. Epub 2019 Aug 9.

Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Purpose: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy, which has demonstrated sensitivity to immune checkpoint inhibitor therapy. Here, we perform the largest genomics study in MCC to date to characterize the molecular landscape and evaluate for clinical and molecular correlates to immune checkpoint inhibitor response.

Experimental Design: Comprehensive molecular profiling was performed on 317 tumors from patients with MCC, including the evaluation of oncogenic mutations, tumor mutational burden (TMB), mutational signatures, and the Merkel cell polyomavirus (MCPyV). For a subset of 57 patients, a retrospective analysis was conducted to evaluate for clinical and molecular correlates to immune checkpoint inhibitor response and disease survival.

Results: Genomic analyses revealed a bimodal distribution in TMB, with 2 molecularly distinct subgroups. Ninety-four percent ( = 110) of TMB-high specimens exhibited an ultraviolet light (UV) mutational signature. MCPyV genomic DNA sequences were not identified in any TMB-high cases (0/117), but were in 63% (110/175) of TMB-low cases. For 36 evaluable patients treated with checkpoint inhibitors, the overall response rate was 44% and response correlated with survival at time of review (100% vs. 20%, < 0.001). Response rate was 50% in TMB-high/UV-driven and 41% in TMB-low/MCPyV-positive tumors ( = 0.63). Response rate was significantly correlated with line of therapy: 75% in first-line, 39% in second-line, and 18% in third-line or beyond ( = 0.0066). PD-1, but not PD-L1, expression was associated with immunotherapy response (77% vs. 21%, = 0.00598, for PD-1 positive and negative, respectively).

Conclusions: We provide a comprehensive genomic landscape of MCC and demonstrate clinicogenomic associates of immunotherapy response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-4159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774882PMC
October 2019

Neoadjuvant BRAF-targeted therapy in regionally advanced and oligometastatic melanoma.

Pigment Cell Melanoma Res 2020 01 12;33(1):86-95. Epub 2019 Sep 12.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.

Current management of locoregional and oligometastatic melanoma is typically with surgery; however, some patients are unable to undergo resection due to location/size of their tumors and/or the anticipated morbidity of the surgery. While there are currently no established guidelines for neoadjuvant therapy in melanoma, neoadjuvant BRAF-targeted therapy may make resection more feasible. A retrospective analysis was conducted of 23 patients with BRAFV600-mutant, stage III/IV melanoma treated with BRAF-targeted therapy prior to surgery, with no adjuvant treatment. Surgical specimens, preoperative imaging, and clinical outcomes were evaluated. Results: Ten of 23 patients (44%) attained a pathologic complete response (pCR), with no correlation between RECIST response based on preoperative imaging and pathologic response. After a median of 43-month follow-up, only 1 patient (10%) with a pCR recurred, while 8 of 13 (62%) patients without a pCR recurred. Patients with a pCR had significantly improved relapse-free (RFS) and overall survival (OS) compared to patients with residual tumor. Neoadjuvant BRAF-targeted therapy is associated with a high pCR rate in patients with stage III-IV melanoma, which may correlate with improved RFS and OS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pcmr.12813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928428PMC
January 2020

Clinical, pathological, and genomic features of EWSR1-PATZ1 fusion sarcoma.

Mod Pathol 2019 11 12;32(11):1593-1604. Epub 2019 Jun 12.

Sarcoma Department, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Molecular diagnostics of sarcoma subtypes commonly involve the identification of characteristic oncogenic fusions. EWSR1-PATZ1 is a rare fusion partnering in sarcoma, with few cases reported in the literature. In the current study, a series of 11 cases of EWSR1-PATZ1 fusion positive malignancies are described. EWSR1-PATZ1-related sarcomas occur across a wide age range and have a strong predilection for chest wall primary site. Secondary driver mutations in cell-cycle genes, and in particular CDKN2A (71%), are common in EWSR1-PATZ1 sarcomas in this series. In a subset of cases, an extended clinical and histopathological review was performed, as was confirmation and characterization of the fusion breakpoint revealing a novel intronic pseudoexon sequence insertion. Unified by a shared gene fusion, EWSR1-PATZ1 sarcomas otherwise appear to exhibit divergent morphology, a polyphenotypic immunoprofile, and variable clinical behavior posing challenges for precise classification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-019-0301-1DOI Listing
November 2019

Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy.

J Clin Oncol 2019 03 6;37(9):693-702. Epub 2019 Feb 6.

14 Fred Hutchinson Cancer Research Center/Cancer Immunotherapy Trials Network, Seattle, WA.

Purpose: Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited.

Patients And Methods: In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Results: Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus-positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death.

Conclusion: Here, we present the longest observation to date of patients with aMCC receiving first-line anti-programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.01896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424137PMC
March 2019

Early objective response to avelumab treatment is associated with improved overall survival in patients with metastatic Merkel cell carcinoma.

Cancer Immunol Immunother 2019 Apr 5;68(4):609-618. Epub 2019 Feb 5.

Merck KGaA, Darmstadt, Germany.

Background: Response rates are primary endpoints in many oncology trials; however, correlation with overall survival (OS) is not uniform across cancer types, treatments, or lines of therapy. This study explored the association between objective response (OR) and OS in patients with chemotherapy-refractory metastatic Merkel cell carcinoma who received avelumab (anti-PD-L1).

Methods: Eighty-eight patients enrolled in JAVELIN Merkel 200 (part A; NCT02155647) received i.v. avelumab 10 mg/kg every 2 weeks until confirmed progression, unacceptable toxicity, or withdrawal. Using conditional landmark analyses, we compared OS in patients with and without confirmed OR (RECIST v1.1). We applied a Cox model that included OR as a time-varying covariate and adjusted for age, visceral disease, and number of previous therapies.

Results: Twenty-nine patients had confirmed OR; 20 by study week 7 and 7 more between study weeks 7 and 13. Survival probabilities 18 months after treatment initiation were 90% [95% confidence interval (CI) 65.6-97.4] in patients with OR at week 7 and 26.2% (95% CI 15.7-37.8) in patients without OR but who were alive at week 7. Median OS was not reached in patients with OR and was 8.8 months (95% CI 6.4-12.9) in patients without. Similar results were observed for the week 13 landmark. The adjusted Cox model showed OR was associated with a 95% risk reduction of death [hazard ratio 0.052 (95% CI 0.018-0.152)] compared with a nonresponse.

Conclusions: Patients with OR by 7 or 13 weeks had significantly longer OS than patients without, confirming that early OR is an endpoint of major importance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-018-02295-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447510PMC
April 2019

Precision medicine approaches for the management of Ewing sarcoma: current perspectives.

Pharmgenomics Pers Med 2019 17;12:9-14. Epub 2019 Jan 17.

Sarcoma Department,

Advancements in molecular and genetic techniques have significantly furthered our biological understanding of Ewing sarcoma (ES). ES is typified by a driving TET-ETS fusion with an otherwise relatively quiet genome. Detection of one of several characteristic fusions, most commonly , is the gold standard for diagnosis. We discuss the current role of precision medicine in the diagnosis, treatment, and monitoring of ES. Continued efforts toward molecularly guided approaches are actively being pursued in ES to better refine prognosis, identify germline markers of disease susceptibility, influence therapeutic selection, effectively monitor disease activity in real time, and identify genetic and immunotherapeutic targets for therapeutic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/PGPM.S170612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340366PMC
January 2019

Chromosome 19 miRNA cluster and CEBPB expression specifically mark and potentially drive triple negative breast cancers.

PLoS One 2018 18;13(10):e0206008. Epub 2018 Oct 18.

Sarcoma Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States of America and.

Triple negative breast cancers (TNBCs) are known to express low PGR, ESR1, and ERBB2, and high KRT5, KRT14, and KRT17. However, the reasons behind the increased expressions of KRT5, KRT14, KRT17 and decreased expressions of PGR, ESR1, and ERBB2 in TNBCs are not fully understood. Here we show that, expression of chromosome 19 miRNA cluster (C19MC) specifically marks human TNBCs. Low REST and high CEBPB correlate with expression of C19MC, KRT5, KRT14, and KRT17 and enhancers of these genes/cluster are regulated by CEBPB and REST binding sites. The C19MC miRNAs in turn can potentially target REST to offer a positive feedback loop, and might target PGR, ESR1, ERBB2, GATA3, SCUBE2, TFF3 mRNAs to contribute towards TNBC phenotype. Thus our study demonstrates that C19MC miRNA expression marks TNBCs and that C19MC miRNAs and CEBPB might together determine the TNBC marker expression pattern.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206008PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193703PMC
April 2019

Identification of a novel MTAP-RAF1 fusion in a soft tissue sarcoma.

Diagn Pathol 2018 Oct 12;13(1):77. Epub 2018 Oct 12.

Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, FOB1, Tampa, Florida, 33612, USA.

Background: RAF family activating fusions have been described as a potentially targetable molecular finding in a subset of soft tissue sarcomas. To further expand upon the landscape of this genetic feature, we describe a novel MTAP-RAF1 activating fusion identified in a S100 positive soft tissue sarcoma.

Case Presentation: A 51 year old man underwent excision of a soft tissue mass in his foot. Pathology revealed a spindle cell neoplasm with S100 positivity, ultimately classified as a soft tissue sarcoma, not otherwise specified. Comprehensive molecular profiling was performed to help establish the diagnosis and revealed a novel MTAP-RAF1 fusion that includes the tyrosine kinase domain of RAF1.

Conclusions: Our report adds to the spectrum of fusion-driven RAF activation observed in soft tissue sarcomas and lends additional evidence that RAF activation plays an important role in some soft tissue sarcomas. Identification of novel fusions involving the MAPK/ERK pathway in sarcomas may provide new avenues for precision medicine strategies involving targeted kinase inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13000-018-0759-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186031PMC
October 2018

Checkpoint inhibitor-associated cutaneous small vessel vasculitis.

JAAD Case Rep 2018 Aug 11;4(7):675-677. Epub 2018 Aug 11.

University of South Florida Morsani College of Medicine, Tampa, Florida.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jdcr.2018.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092526PMC
August 2018

Response to Checkpoint Inhibitor Therapy in Advanced Classic Kaposi Sarcoma: A Case Report and Immunogenomic Study.

J Natl Compr Canc Netw 2018 07;16(7):797-800

Kaposi sarcoma (KS) is an uncommon angioproliferative malignancy that is associated with human herpesvirus 8. Although there has been recent enthusiasm for evaluating immune checkpoint inhibition as a therapeutic option for viral-associated tumors, the clinical utility in this disease is currently unknown. We report a case of advanced classic KS refractory to multiple lines of chemotherapy that experienced a partial response to anti-PD-1 therapy. Comprehensive molecular profiling was performed on a diagnostic tumor biopsy sample. Molecular profiling data from 8 additional male patients with KS were reviewed and compared with those of the index case. The genomic profile of the index case was notable for higher-than-typical somatic mutational burden, including pathogenic mutation in multiple well-described cancer genes, such as , and Our case suggests that further clinical study of checkpoint inhibitor therapy in classic KS is warranted, and provides a hypothesis for future immunogenomic biomarker analysis in this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2018.7018DOI Listing
July 2018

Combined BRAF and HSP90 Inhibition in Patients with Unresectable -Mutant Melanoma.

Clin Cancer Res 2018 11 19;24(22):5516-5524. Epub 2018 Apr 19.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.

BRAF inhibitors are clinically active in patients with advanced BRAF-mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888. Vemurafenib (960 mg p.o. b.i.d.) combined with escalating doses of XL888 (30, 45, 90, or 135 mg p.o. twice weekly) was investigated in 21 patients with advanced BRAF-mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity. Objective responses were observed in 15 of 20 evaluable patients [75%; 95% confidence interval (CI), 51%-91%], with 3 complete and 12 partial responses. Median progression-free survival and overall survival were 9.2 months (95% CI, 3.8-not reached) and 34.6 months (6.2-not reached), respectively. The most common grade 3/4 toxicities were skin toxicities, such as rash ( = 4, 19%) and cutaneous squamous cell carcinomas ( = 3, 14%), along with diarrhea ( = 3, 14%). Pharmacodynamic analysis of patients' peripheral blood mononuclear cells (PBMC) showed increased day 8 HSP70 expression compared with baseline in the three cohorts with XL888 doses ≥45 mg. Diverse effects of vemurafenib-XL888 upon intratumoral HSP client protein expression were noted, with the expression of multiple proteins (including ERBB3 and BAD) modulated on therapy. XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAF-mutant melanoma, with a tolerable side-effect profile. HSP90 inhibitors warrant further evaluation in combination with current standard-of-care BRAF plus MEK inhibitors in BRAF-mutant melanoma. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-0565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195480PMC
November 2018

Combination of Ipilimumab and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma.

Front Oncol 2018 2;8:44. Epub 2018 Mar 2.

Immunology Department, Moffitt Cancer Center, Tampa, FL, United States.

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) for metastatic melanoma can be highly effective, but attrition due to progression before TIL administration (32% in prior institutional experience) remains a limitation. We hypothesized that combining ACT with cytotoxic T lymphocyte-associated antigen 4 blockade would decrease attrition and allow more patients to receive TIL.

Experimental Design: Thirteen patients with metastatic melanoma were enrolled. Patients received four doses of ipilimumab (3 mg/kg) beginning 2 weeks prior to tumor resection for TIL generation, then 1 week after resection, and 2 and 5 weeks after preconditioning chemotherapy and TIL infusion followed by interleukin-2. The primary endpoint was safety and feasibility. Secondary endpoints included of clinical response at 12 weeks and at 1 year after TIL transfer, progression free survival (PFS), and overall survival (OS).

Results: All patients received at least two doses of ipilimumab, and 12 of the 13 (92%) received TIL. A median of 6.5 × 10 (2.3 × 10 to 1.0 × 10) TIL were infused. At 12 weeks following infusion, there were five patients who experienced objective response (38.5%), four of whom continued in objective response at 1 year and one of which became a complete response at 52 months. Median progression-free survival was 7.3 months (95% CI 6.1-29.9 months). Grade ≥ 3 immune-related adverse events included hypothyroidism (3), hepatitis (2), uveitis (1), and colitis (1).

Conclusion: Ipilimumab plus ACT for metastatic melanoma is feasible, well tolerated, and associated with a low rate of attrition due to progression during cell expansion. This combination approach serves as a model for future efforts to improve the efficacy of ACT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2018.00044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840208PMC
March 2018
-->