Publications by authors named "Jonathan Reichel"

10 Publications

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-Mutated Prostate Cancer: Clinical Outcomes With Standard Therapies and Immune Checkpoint Blockade.

JCO Precis Oncol 2020 21;4:382-392. Epub 2020 Apr 21.

University of Michigan, Ann Arbor, MI.

Purpose: Translational studies have shown that mutations may delineate an immunoresponsive subgroup of prostate cancer, characterized by high neo-antigen burden. Given that these mutations may define a clinically distinct subgroup, we sought to describe outcomes to standard drugs and checkpoint inhibitors (CPI).

Patients And Methods: Clinical data from consecutive patients with mutations were retrospectively collected from 7 centers. Several clinical-grade sequencing assays were used to assess CDK12 status. Descriptive statistics included PSA50 response rate (≥ 50% decline in prostate-specific antigen from baseline) and clinical/radiographic progression-free survival (PFS).

Results: Of 52 patients with -mutated prostate cancer, 27 (52%) had detected biallelic CDK12 alterations. At diagnosis, 44 (88%) had Gleason grade group 4-5, 52% had T3-T4, and 14 (27%) had M1 disease. Median follow-up was 8.2 years (95% CI, 5.6 to 11.1 years), and 49 (94%) developed metastatic disease. Median overall survival from metastasis was 3.9 years (95% CI, 3.2 to 8.1 years). Unconfirmed PSA50 response rates to abiraterone and enzalutamide in the first-line castration-resistant prostate cancer setting were 11 of 17 (65%) and 9 of 12 (75%), respectively. Median PFS on first-line abiraterone and enzalutamide was short, at 8.2 months (95% CI, 6.6 to 12.6 months) and 10.6 months (95% CI, 10.2 months to not reached), respectively. Nineteen patients received CPI therapy. PSA50 responses to CPI were noted in 11%, and PFS was short; however, the estimated 9-month PFS was 23%. PFS was higher in chemotherapy-näıve versus chemotherapypretreated patients (median PFS: not reached v 2.1 months, = .004).

Conclusion: mutations define an aggressive prostate cancer subgroup, with a high rate of metastases and short overall survival. CPI may be effective in a minority of these patients, and exploratory analysis supports using anti-programmed cell death protein 1 drugs early. Prospective studies testing CPI in this subset of patients with prostate cancer are warranted.
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http://dx.doi.org/10.1200/po.19.00383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363399PMC
April 2020

Peripheral Circulating Tumor DNA Detection Predicts Poor Outcomes After Liver Resection for Metastatic Colorectal Cancer.

Ann Surg Oncol 2019 Jun 31;26(6):1824-1832. Epub 2019 Jan 31.

Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Liver resection can be curative for well-selected metastatic colorectal cancer (CRC) patients. Circulating tumor DNA (ctDNA) has shown promise as a biomarker for tumor dynamics and recurrence following CRC resection. This prospective pilot study investigated the use of ctDNA to predict disease outcome in resected CRC patients.

Methods: Between November 2014 and November 2015, 60 patients with CRC were identified and prospectively enrolled. During liver resection, blood was drawn from peripheral (PERIPH), portal (PV), and hepatic (HV) veins, and 3-4 weeks postoperatively from a peripheral vein (POSTOP). Kappa statistics were used to compare mutated (mt) genes in tissue and ctDNA. Disease-specific and disease-free survival (DSS and DFS) were assessed from surgery with Kaplan-Meier and Cox methods.

Results: For the 59 eligible patients, the most commonly mutated genes were TP53 (mtTP53: 47.5%) and APC (mtAPC: 50.8%). Substantial to almost-perfect agreement was seen between ctDNA from PERIPH and PV (mtTP53: 89.8%, κ = 0.73, 95% confidence interval [CI] 0.53-0.93; mtAPC: 94.9%, κ = 0.83, 95% CI 0.64-1.00), as well as HV (mtTP53: 91.5%, κ = 0.78, 95% CI 0.60-0.96; mtAPC: 91.5%, κ = 0.73, 95% CI 0.51-0.95). Tumor mutations and PERIPH ctDNA had fair-to-moderate agreement (mtTP53: 72.9%, κ = 0.44, 95% CI 0.23-0.66; mtAPC: 61.0%, κ = 0.23, 95% CI 0.04-0.42). Detection of PERIPH mtTP53 was associated with worse 2-year DSS (mt+ 79% vs. mt- 90%, P = 0.024).

Conclusions: Peripheral blood reflects the perihepatic ctDNA signature. Disagreement between tissue and ctDNA mutations may reflect the true natural history of tumor genes or an assay limitation. Peripheral ctDNA detection before liver resection is associated with worse DSS.
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http://dx.doi.org/10.1245/s10434-019-07201-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511310PMC
June 2019

Flow-sorting and Exome Sequencing of the Reed-Sternberg Cells of Classical Hodgkin Lymphoma.

J Vis Exp 2017 06 10(124). Epub 2017 Jun 10.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center;

The Hodgkin Reed-Sternberg cells of classical Hodgkin lymphoma are sparsely distributed within a background of inflammatory lymphocytes and typically comprise less than 1% of the tumor mass. Material derived from bulk tumor contains tumor content at a concentration insufficient for characterization. Therefore, fluorescence activated cell sorting using eight antibodies, as well as side- and forward-scatter, is described here as a method of rapidly separating and concentrating with high purity thousands of HRS cells from the tumor for subsequent study. At the same time, because standard protocols for exome sequencing typically require 100-1,000 ng of input DNA, which is often too high, even with flow sorting, we also provide an optimized, low-input library construction protocol capable of producing high-quality data from as little as 10 ng of input DNA. This combination is capable of producing next-generation libraries suitable for hybridization capture of whole-exome baits or more focused targeted panels, as desired. Exome sequencing of the HRS cells, when compared against healthy intratumor T or B cells, can identify somatic alterations, including mutations, insertions and deletions, and copy number alterations. These findings elucidate the molecular biology of HRS cells and may reveal avenues for targeted drug treatments.
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http://dx.doi.org/10.3791/54399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608337PMC
June 2017

Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies.

J Clin Invest 2017 Jun 15;127(6):2066-2080. Epub 2017 May 15.

Department of Pathology and Laboratory Medicine.

Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase-inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further, we observed that 6-ETI induces ATP depletion and cell death accompanied by S phase arrest and DNA damage only in ADK-expressing cells. Immunohistochemistry for ADK served as a biomarker approach to identify 6-ETI-sensitive tumors, which we documented for other lymphoid malignancies with plasmacytic features. Notably, multiple myeloma (MM) expresses high levels of ADK, and 6-ETI was toxic to MM cell lines and primary specimens and had a robust antitumor effect in a disseminated MM mouse model. Several nucleoside analogs are effective in treating leukemias and T cell lymphomas, and 6-ETI may fill this niche for the treatment of PEL, plasmablastic lymphoma, MM, and other ADK-expressing cancers.
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http://dx.doi.org/10.1172/JCI83936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451239PMC
June 2017

AKT Inhibition in Solid Tumors With AKT1 Mutations.

J Clin Oncol 2017 Jul 10;35(20):2251-2259. Epub 2017 May 10.

David M. Hyman, Lillian M. Smyth, Mark T.A. Donoghue, Matthew T. Chang, Jonathan B. Reichel, Nancy Bouvier, S. Duygu Selcuklu, Tara E. Soumerai, Jean Torrisi, Joseph P. Erinjeri, Michael F. Berger, Sarat Chandarlapaty, David B. Solit, José Baselga, and Barry S. Taylor, Memorial Sloan Kettering Cancer Center; David B. Solit, Weill Cornell Medical College, Cornell University, New York, NY; J. Carl Barrett and Brian Dougherty, AstraZeneca, Waltham, MA; Helen Ambrose, Andrew Foxley, Justin P.O. Lindemann, Robert McEwen, Martin Pass, and Gaia Schiavon, AstraZeneca, Cambridge; Emma J. Dean, The Christie National Health Service Foundation, Manchester; Udai Banerji, Royal Marsden Hospital, London, United Kingdom; Shannon N. Westin, The University of Texas MD Anderson Cancer Center, Houston, TX; Philippe L. Bedard, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hideaki Bando, National Cancer Center East Hospital, Kashiwa, Japan; Anthony B. El-Khoueiry, University of Southern California Norris Comprehensive Cancer Center; Alain Mita, Cedars-Sinai Medical Center, Los Angeles, CA; José A. Pérez-Fidalgo, Hospital Clinico de Valencia, Valencia, Spain; and Jan H.M. Schellens, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K-mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor-positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.
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http://dx.doi.org/10.1200/JCO.2017.73.0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501365PMC
July 2017

Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells.

Blood 2015 Feb 8;125(7):1061-72. Epub 2014 Dec 8.

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;

Classical Hodgkin lymphoma (cHL) is characterized by sparsely distributed Hodgkin and Reed-Sternberg (HRS) cells amid reactive host background, complicating the acquisition of neoplastic DNA without extensive background contamination. We overcame this limitation by using flow-sorted HRS and intratumor T cells and optimized low-input exome sequencing of 10 patient samples to reveal alterations in genes involved in antigen presentation, chromosome integrity, transcriptional regulation, and ubiquitination. β-2-microglobulin (B2M) is the most commonly altered gene in HRS cells, with 7 of 10 cases having inactivating mutations that lead to loss of major histocompatibility complex class I (MHC-I) expression. Enforced wild-type B2M expression in a cHL cell line restored MHC-I expression. In an extended cohort of 145 patients, the absence of B2M protein in the HRS cells was associated with lower stage of disease, younger age at diagnosis, and better overall and progression-free survival. B2M-deficient cases encompassed most of the nodular sclerosis subtype cases and only a minority of mixed cellularity cases, suggesting that B2M deficiency determines the tumor microenvironment and may define a major subset of cHL that has more uniform clinical and morphologic features. In addition, we report previously unknown genetic alterations that may render selected patients sensitive to specific targeted therapies.
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http://dx.doi.org/10.1182/blood-2014-11-610436DOI Listing
February 2015

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma.

Blood 2014 Nov 17;124(20):3118-29. Epub 2014 Sep 17.

Institute of Physiological Chemistry, University of Ulm, Ulm, Germany;

The survival of classical Hodgkin lymphoma (cHL) cells depends on activation of NF-κB, JAK/STAT, and IRF4. Whereas these factors typically induce the master regulator of plasma cell (PC) differentiation PRDM1/BLIMP-1, levels of PRDM1 remain low in cHL. FOXO1, playing a critical role in normal B-cell development, acts as a tumor suppressor in cHL, but has never been associated with induction of PC differentiation. Here we show that FOXO1 directly upregulates the full-length isoform PRDM1α in cHL cell lines. We also observed a positive correlation between FOXO1 and PRDM1 expression levels in primary Hodgkin-Reed-Sternberg cells. Further, we show that PRDM1α acts as a tumor suppressor in cHL at least partially by blocking MYC. Here we provide a link between FOXO1 repression and PRDM1α downregulation in cHL and identify PRDM1α as a tumor suppressor in cHL. The data support a potential role for FOXO transcription factors in normal PC differentiation.
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http://dx.doi.org/10.1182/blood-2014-07-590570DOI Listing
November 2014

Transforming fusions of FGFR and TACC genes in human glioblastoma.

Science 2012 Sep 26;337(6099):1231-5. Epub 2012 Jul 26.

Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.

The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition.
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http://dx.doi.org/10.1126/science.1220834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677224PMC
September 2012

Magnetic nanotubes for magnetic-field-assisted bioseparation, biointeraction, and drug delivery.

J Am Chem Soc 2005 May;127(20):7316-7

Department of Chemistry & Biochemistry, University of Maryland, College Park, 20742, USA.

Tubular structure of nanoparticles is highly attractive due to their structural attributes, such as the distinctive inner and outer surfaces, over conventional spherical nanoparticles. Inner voids can be used for capturing, concentrating, and releasing species ranging in size from large proteins to small molecules. Distinctive outer surfaces can be differentially functionalized with environment-friendly and/or probe molecules to a specific target. Magnetic particles have been extensively studied in the field of biomedical and biotechnological applications, including drug delivery, biosensors, chemical and biochemical separation and concentration of trace amounts of specific targets, and contrast enhancement in magnetic resonance imaging (MRI). Therefore, by combining the attractive tubular structure with magnetic property, the magnetic nanotube (MNT) can be an ideal candidate for the multifunctional nanomaterial toward biomedical applications, such as targeting drug delivery with MRI capability. Here, we successfully synthesized magnetic silica-iron oxide composite nanotubes and demonstrated the magnetic-field-assisted chemical and biochemical separations, immunobinding, and drug delivery.
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http://dx.doi.org/10.1021/ja0517365DOI Listing
May 2005

Muscle strength response to strength training is influenced by insulin-like growth factor 1 genotype in older adults.

J Appl Physiol (1985) 2005 Jun;98(6):2147-54

Department of Kinesiology, University of Maryland, College Park, MD 20742, USA.

Strength training (ST) is considered an intervention of choice for the prevention and treatment of sarcopenia. Reports in the literature have suggested that the insulin-like growth factor I protein (IGF-I) plays a major role in ST-induced skeletal muscle hypertrophy and strength improvements. A microsatellite repeat in the promoter region of the IGF1 gene has been associated with IGF-I blood levels and phenotypes related to IGF-I in adult men and women. To examine the influence of this polymorphism on muscle hypertrophic and strength responses to ST, we studied 67 Caucasian men and women before and after a 10-wk single-leg knee-extension ST program. One repetition maximum strength, muscle volume via computed tomography, and muscle quality were assessed at baseline and after 10 wk of training. The IGF1 repeat promoter polymorphism and three single-nucleotide polymorphisms were genotyped. For the promoter polymorphism, subjects were grouped as homozygous for the 192 allele, heterozygous, or noncarriers of the 192 allele. After 10 wk of training, 1-repetition maximum, muscle volume, and muscle quality increased significantly for all groups combined (P < 0.001). However, carriers of the 192 allele gained significantly more strength with ST than noncarriers of the 192 allele (P = 0.02). There was also a nonsignificant trend for a greater increase in muscle volume in 192 carriers than noncarriers (P = 0.08). No significant associations were observed for the other polymorphisms studied. Thus these data suggest that the IGF1 promoter polymorphism may influence the strength response to ST. Larger sample sizes should be used in future studies to verify these results.
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http://dx.doi.org/10.1152/japplphysiol.00817.2004DOI Listing
June 2005