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Dana-Farber Research Publication 6.15.2022

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June 15, 2022

This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: Michael_buller@dfci.harvard.edu.

Journal of Clinical Oncology

Apoptosis: Directly Targeted at Last

Letai A

Every cell in our bodies is encoded with pathways of programmed cell death so that useless or harmful cells can be eliminated for the benefit of the organism as a whole. Among these, the mitochondrial pathway of apoptosis is prominent for its role in oncogenesis and response to cancer therapy. The selective activation of apoptosis in cancer cells has been an important goal in oncology for decades. Recently, a class of drugs called BH3 mimetics has emerged. In the original report that accompanies this article, Harrison et al present another novel application of BH3 mimetic therapy with navitoclax in the context of myelofibrosis.


Journal of Clinical Oncology

Circulating Tumor DNA as a Biomarker in Patients with Stage III and IV Wilms Tumor: Analysis from a Children's Oncology Group Trial, AREN0533

Madanat-Harjuoja LM, Klega K, Thorner AR, Nag A, Diller LR, Mullen EA, Crompton BD

PURPOSE: The utility of circulating tumor DNA (ctDNA) analyses has not been established in the risk stratification of Wilms tumor (WT). We evaluated the detection of ctDNA and selected risk markers in the serum and urine of patients with WT and compared findings with those of matched diagnostic tumor samples.
PATIENTS AND METHODS: Fifty of 395 children with stage III or IV WT enrolled on Children's Oncology Group trial AREN0533 had banked pretreatment serum, urine, and tumor available. Next-generation sequencing was used to detect ctDNA. Copy-number changes in 1q, 16q, and 1p, and single-nucleotide variants in serum and urine were compared with tumor biopsy data. Event-free survival (EFS) was compared between patients with and without ctDNA detection.
RESULTS: ctDNA was detected in the serum of 41/50 (82%) and in the urine in 13/50 (26%) patients. Agreement between serum ctDNA detection and tumor sequencing results was as follows: 77% for 1q gain, 88% for 16q deletions, and 70% for 1p deletions, with ĸ-coefficients of 0.56, 0.74, and 0.29, respectively. Sequencing also demonstrated that single-nucleotide variants detected in tumors could be identified in the ctDNA. There was a trend toward worse EFS in patients with ctDNA detected in the serum (4-year EFS 80% v 100%, P = .14).
CONCLUSION: ctDNA demonstrates promise as an easily accessible prognostic biomarker with potential to detect tumor heterogeneity. The observed trend toward more favorable outcome in patients with undetectable ctDNA requires validation. ctDNA profiling should be further explored as a noninvasive diagnostic and prognostic tool in the risk-adapted treatment of patients with WT.


Journal of Clinical Oncology

Exercise, Diet, and Weight Management During Cancer Treatment: ASCO Guideline

Ligibel JA, Meyerhardt JA

PURPOSE: To provide guidance on exercise, diet, and weight management during active cancer treatment in adults.
METHODS: A systematic review of the literature identified systematic reviews and randomized controlled trials evaluating the impact of aerobic and resistance exercise, specific diets and foods, and intentional weight loss and avoidance of weight gain in adults during cancer treatment, on quality of life, treatment toxicity, and cancer control. PubMed and the Cochrane Library were searched from January 2000 to May 2021. ASCO convened an Expert Panel to review the evidence and formulate recommendations.
RESULTS: The evidence base consisted of 52 systematic reviews (42 for exercise, nine for diet, and one for weight management), and an additional 23 randomized controlled trials. The most commonly studied types of cancer were breast, prostate, lung, and colorectal. Exercise during cancer treatment led to improvements in cardiorespiratory fitness, strength, fatigue, and other patient-reported outcomes. Preoperative exercise in patients with lung cancer led to a reduction in postoperative length of hospital stay and complications. Neutropenic diets did not decrease risk of infection during cancer treatment.
RECOMMENDATIONS: Oncology providers should recommend regular aerobic and resistance exercise during active treatment with curative intent and may recommend preoperative exercise for patients undergoing surgery for lung cancer. Neutropenic diets are not recommended to prevent infection in patients with cancer during active treatment. Evidence for other dietary and weight loss interventions during cancer treatment was very limited. The guideline discusses special considerations, such as exercise in individuals with advanced cancer, and highlights the critical need for more research in this area, particularly regarding diet and weight loss interventions during cancer treatment. Additional information is available at www.asco.org/supportive-care-guidelines.


Nature

A Vaccine Targeting Resistant Tumours by Dual T Cell Plus NK Cell Attack

Badrinath S, Dellacherie MO, Li A, Zheng S, Zhang X, Sobral M, Pyrdol JW, Smith KL, Lu Y, Haag S, Ijaz H, Dranoff G, Yuan GC, Mooney DJ, Wucherpfennig KW

Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.


Nature Communications

STING Agonism Reprograms Tumor-Associated Macrophages and Overcomes Resistance to PARP Inhibition in BRCA1-Deficient Models of Breast Cancer

Wang Q, Bergholz JS, Ding L, Lin Z, Kabraji SK, Hughes ME, He X, Xie S, Jiang T, Wang W, Zoeller JJ, Kim HJ, Roberts TM, Konstantinopoulos PA, Matulonis UA, Dillon DA, Winer EP, Lin NU, Zhao JJ

PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.


American Journal of Dermatopathology

Shared Clonal Origin of Multiple Histiocytic and Dendritic Neoplasms and Polycythemia Vera, Follicular Lymphoma in 1 Patient

Larocca C, Shanmugam V, Zemmour D, Antin JH, Lane AA


Blood Advances

Organ-Specific Response After Low-Dose Interleukin-2 Therapy for Steroid Refractory Chronic Graft-versus-Host Disease

Kim HT, Koreth J, Whangbo J, Nikiforow S, Reynolds CG, Stowe P, Ho VT, Cutler CS, Antin JH, Soiffer RJ, Ritz J


Bone Marrow Transplantation

Peer Support in Patients with Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplantation (HSCT): A Qualitative Study

Amonoo HL, Harnedy LE, Deary EC, Traeger L, Daskalakis EP, Cutler C, Kelkar AH, Rosales R, Goldschen L, Pirl WF, Feig EH, Revette A, Huffman JC, El-Jawahri A


Bone Marrow Transplantation

Peer Support in Patients with Hematologic Malignancies: A Systematic Review

Amonoo HL, Harnedy LE, Staton SC, Daskalakis E, El-Jawahri A, Huffman JC


Cancer Immunology Research

Comprehensive Characterizations of Immune Receptor Repertoire in Tumors and Cancer Immunotherapy Studies

Song L, Cohen D, Altreuter J, Bai G, Hu X, Livak KJ, Li H, Liu XS


European Journal of Cancer

Impact of MET Status on Treatment Outcomes in Papillary Renal Cell Carcinoma: A Pooled Analysis of Historical Data

Albiges L, Choueiri T, Signoretti S


European Urology Oncology

First-line Systemic Treatment of Recurrent Prostate Cancer After Primary or Salvage Local Therapy: A Systematic Review of the Literature

Sweeney CJ


Genetic Epidemiology

Statistical Methods for Mendelian Models with Multiple Genes and Cancers

Liang JW, Parmigiani G, Braun D


International Journal of Radiation Oncology, Biology, Physics

Stereotactic Magnetic Resonance Guided Adaptive Radiation Therapy (SMART) for Abdominopelvic Oligometastases

Yang DD, Huynh E, Williams CL, Han Z, Ampofo N, Vastola ME, Sangal P, Mak RH, Leeman JE, Huynh MA


International Journal of Radiation Oncology, Biology, Physics

Retrospective Review of Outcomes Following Radiotherapy for Oligoprogressive Disease on Immune Checkpoint Blockade

Mahmood U, Huynh MA, Killoran JH, Qian JM, Bent EH, Aizer AA, Mak RH, Mamon HJ, Balboni TA, Gunasti L, Ott PA, Awad MM, Schoenfeld JD


Journal of Adolescent and Young Adult Oncology

Factors Affecting Hospice Use Among Adolescents and Young Adult Cancer Patients

Mack JW


Journal of Medicinal Chemistry

The Dawn of Allosteric BCR-ABL1 Drugs: From a Phenotypic Screening Hit to an Approved Drug

Teng M, Luskin MR


Journal of Molecular Biology

Eukaryotic Initiation Factor 5A2 Regulates Expression of Antiviral Genes

Farache D, Liu L, Lee ASY


Journal of Palliative Medicine

Differences in End-of-Life Care between COVID-19 Inpatient Decedents with English Proficiency and Limited English Proficiency

Chua IS, Shi SM, Jia Z, Leiter R, Rodriguez JA, Yeh IM, Bernacki R, Levine DM


JCI Insight

Response to Supraphysiological Testosterone is Predicted by a Distinct Androgen Receptor Cistrome

Qiu X, Abou Alaiwi S, Seo JH, El Zarif T, Bell C, O'Connor E, Pomerantz M, Freedman ML, Brown M, Long HW


Nutrients

The Effect of Exercise and Nutritional Interventions on Body Composition in Patients with Advanced or Metastatic Cancer: A Systematic Review

Wilson RL, Gonzalo-Encabo P, Kang DW, Christopher CN, Dieli-Conwright CM


PLoS Computational Biology

Designing Optimal Allocations for Cancer Screening Using Queuing Network Models

Dean J, Goldberg E, Michor F


Psycho-Oncology

Psychosocial Oncology in Sub-Saharan Africa: Lessons from Ghana

Amonoo HL, Longley RM, Jacobo MC, Pirl WF


Radiotherapy and Oncology

Characterization of Clinical Outcomes After Shorter Course Hypofractionated and Standard-Course Radiotherapy for Stage I-III Curatively-Treated Merkel Cell Carcinoma

Liu KX, Milligan MG, Schoenfeld JD, Tishler RB, Ng AK, Devlin PM, Fite E, Hanna GJ, Silk AW, Yoon CH, Thakuria M, Margalit DN


Transplantation and Cellular Therapy

Comparison of Pulmonary Toxicity After Total Body Irradiation- and Busulfan-Based Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation for Pediatric Patients

Liu KX, Poux N, Shin KY, Moore N, Chen YH, Margossian S, Whangbo JS, Duncan CN, Lehmann LE, Marcus KJ