February 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.
Blood
Association of Clonal Hematopoiesis with Chronic Obstructive Pulmonary Disease
Miller PG, Qiao D, Rojas-Quintero J, Honigberg MC, Sperling AS, Gibson CJ, Niroula A, McConkey ME, Sandoval B, Miller BC, Shi W, Viswanathan K, Leventhal M, Werner L, Moll M, Cade BE, Redline S, Sholl L, Neuberg D, Levy BD, Owen CA, Natarajan P, Silverman EK, van Galen P, Tesfaigzi Y, Cho MH, Ebert BL
Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear. We analyzed whole-genome sequencing and whole-exome sequencing data to detect CHIP in 48‚Äâ835 patients, of whom 8444 had moderate to very severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In the COPDGene cohort, individuals with CHIP had risks of moderate-to-severe, severe, or very severe COPD that were 1.6 (adjusted 95% confidence interval [CI], 1.1-2.2) and 2.2 (adjusted 95% CI, 1.5-3.2) times greater than those for noncarriers. These findings were consistently observed in three additional cohorts and meta-analyses of all patients. CHIP was also associated with decreased FEV1% predicted in the COPDGene cohort (mean between-group differences, -5.7%; adjusted 95% CI, -8.8% to -2.6%), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (odds ratio, 1.03 per 10 pack-years; 95% CI, 1.01-1.05 per 10 pack-years) in the meta-analysis of all patients. Inactivation of Tet2 in mouse hematopoietic cells exacerbated the development of emphysema and inflammation in models of cigarette smoke exposure. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.
Cancer Cell
Dangerous Dynamic Duo: Lactic Acid and PD-1 Blockade
Johnson S, Haigis MC, Dougan SK
In this issue of Cancer Cell, Kumagai et al. reveal lactic acid as a mediator of checkpoint blockade resistance. Tumor-derived lactic acid promotes T regulatory cell (Treg) activity and impairs CD8+ T cell function. PD-1 blockade synergizes with lactic acid to enhance Treg suppression and impede antitumor immunity.
Elife
Paraxial Mesoderm Organoids Model Development of Human Somites
Budjan C, Liu S, Gayen S, Pourquie O, Hormoz S
During the development of the vertebrate embryo, segmented structures called somites are periodically formed from the presomitic mesoderm (PSM), and give rise to the vertebral column. While somite formation has been studied in several animal models, it is less clear how well this process is conserved in humans. Recent progress has made it possible to study aspects of human paraxial mesoderm development such as the human segmentation clock in vitro using human pluripotent stem cells (hPSCs), however, somite formation has not been observed in these monolayer cultures. Here, we describe the generation of human paraxial mesoderm (PM) organoids from hPSCs (termed Somitoids), which recapitulate the molecular, morphological and functional features of paraxial mesoderm development, including formation of somite-like structures in vitro. Using a quantitative image-based screen, we identify critical parameters such as initial cell number and signaling modulations that reproducibly yielded formation of somite-like structures in our organoid system. In addition, using single-cell RNA sequencing and 3D imaging, we show that PM organoids both transcriptionally and morphologically resemble their in vivo counterparts and can be differentiated into somite derivatives. Our organoid system is reproducible and scalable, allowing for the systematic and quantitative analysis of human spinal cord development and disease in vitro.
JAMA Oncology
Geospatial Disparities in the Treatment of Curable Breast Cancer Across the US
Hassett MJ, Tramontano AC, Uno H, Punglia RS
IMPORTANCE: Patient factors help explain disparities in breast cancer treatments and outcomes.
OBJECTIVE: To determine the extent to which geospatial variation in initial breast cancer care can be attributed to region vs patient factors with the aim of guiding quality improvement efforts.
DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective population-based cohort study from January 1, 2007, through December 31, 2016, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database that included 31 571 patients diagnosed with stage I to III breast cancer from 2007 through 2013. Five metrics of care delivery were defined: stage I at diagnosis, chemotherapy receipt, radiation therapy receipt, endocrine therapy (ET) initiation (year 1), and ET continuation (years 3-5). Data analysis was performed from January to June 2021.
EXPOSURES: Stage I diagnosis and treatment with chemotherapy, radiation therapy, or ET.
MAIN OUTCOMES AND MEASURES: For each metric, total variance was attributed proportionally to 4 domains-random, patient factors (eg, age, race and ethnicity, socioeconomic status), region (health service area [HSA]), and unexplained-using hierarchical multivariable modeling.
RESULTS: Of 31 571 total patients (median [IQR] age, 71 [68-75] years), 19 391 (61.4%) had stage I disease at diagnosis. Among eligible patients, 17 297 of 21 190 (81.6%) received radiation therapy, 7204 of 9903 (72.8%) received chemotherapy, 13 115 of 26 855 (48.8%) initiated ET, and 13 944 of 26 855 (52.1%) continued ET. Geospatial density (ie, heat) maps highlight regional performance patterns. For all 5 metrics, region/HSA explained more observed variation (24%-48%) than patient factors (1%-4%); the largest share of variation was unexplained (35%-54%). The metrics with the largest proportion of total variance attributed to region/HSA were ET initiation and continuation (28% and 39%, respectively).
CONCLUSIONS AND RELEVANCE: In this cohort study, there was substantial unexplained geospatial variation in initial breast cancer care. The variance attributed to region/HSA was multifold larger than that explained by patient factors. The importance of patient factors such as race and ethnicity notwithstanding, future quality improvement efforts should focus on reducing unwarranted geospatial variation, especially including optimizing the delivery of ET in low-performing regions.
Journal of Clinical Oncology
Reply to W. E. Rosa et al and T. N. Townsend et al
Enzinger AC, Keating NL, Landrum MB, Wright AA
In response to our article, Dr Rosa et al provide a sobering reminder of the vast global inequities in opioid access. Less than 0.04% of the global prescription opioid supply is distributed to low-income countries, and more than 70% of patients with cancer live in countries where opioid analgesics are almost entirely unavailable. These disturbing figures underpin unimaginable suffering for millions of patients in low- and middle-income countries. We share the authors' concerns that well-intended but short-sighted opioid policies could hamper efforts to provide quality palliative care globally.
ew England Journal of Medicine
Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer
Jänne PA
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively.
METHODS: We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.
RESULTS: A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.
CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).
Proceedings of the National Academy of Science of the USA
Bakht MK, Venkadakrishnan VB, Ku SY, Beltran H
Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating glutamate-ureido-lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based PSMA tracers are still reported to have the potential to identify NEPC metastatic tumors. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We have identified the up-regulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in PSMA-suppressed prostate cancers and find that their expression levels inversely correlate with PSMA expression and are associated with GUL-based radiotracer uptake. Furthermore, we identify that NAALADaseL and mGluR expression correlates with a unique cell cycle signature. This provides an opportunity for the future study of the biology of NEPC and potential therapeutic directions. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a fluorescent PSMA tracer to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL, and specific mGluRs associated with poor prognosis.
Proceedings of the National Academy of Science of the USA
Inhibition of EZH2 Transactivation Function Sensitizes Solid Tumors to Genotoxic Stress
Chen CH, Xiao T, Shah N, Feit A, Xu H, Li W, Mei S, Pierre RS, Shu S, Fei T, Duarte M, Zhao J, Bradner JE, Polyak K, Kantoff PW, Long H, Balk SP, Liu XS, Brown M, Xu K
Drugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring EZH2 gain-of-function mutations that enhance its polycomb repressive function. We have previously reported that EZH2 can act as a transcriptional activator in castration-resistant prostate cancer (CRPC). Now we show that EZH2 inhibitors can also block the transactivation activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomics profiling of cells treated with EZH2 inhibitors demonstrated that in addition to derepressing gene expression, these compounds also robustly down-regulate a set of DNA damage repair (DDR) genes, especially those involved in the base excision repair (BER) pathway. Methylation of the pioneer factor FOXA1 by EZH2 contributes to the activation of these genes, and interaction with the transcriptional coactivator P300 via the transactivation domain on EZH2 directly turns on the transcription. In addition, CRISPR-Cas9-mediated knockout screens in the presence of EZH2 inhibitors identified these BER genes as the determinants that underlie the growth-inhibitory effect of EZH2 inhibitors. Interrogation of public data from diverse types of solid tumors expressing wild-type EZH2 demonstrated that expression of DDR genes is significantly correlated with EZH2 dependency and cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhances their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential combination cancer therapies.
Annals of Surgical Oncology
Weiss A, King C, Grossmith S, Portnow L, Raza S, Nakhlis F, Dominici L, Barbie T, Minami C, Nimbkar S, Rhei E, Mittendorf EA, King TA
Blood Advances
Versluis J, Flamand Y, Haydu JE, Belizaire R, Vedula RS, Charles A, Copson KM, Rozental A, Bendapudi P, Stone RM, DeAngelo DJ, Neuberg D, Luskin MR, Lindsley RC
Blood Advances
Aziz-Bose R, Wachter F, Chiarle R, Lindeman NI, Kim AS, Degar B, Davies K, Pikman Y
Brachytherapy
Lee LJ, Alban GM, Cheng T, Buzurovic I, Pretz J, Singer L, King MT
Breast Cancer Research and Treatment
Seah DS, Tayob N, Leone JP, Hu J, Yin J, Hughes M, Scott SM, Lederman RI, Frank E, Sohl JJ, Erick TK, Peppercorn J, Winer EP, Silverman SG, Come SE, Lin NU
Cancer Treatment Reviews
Global Challenges and Policy Solutions in Breast Cancer Control
Trapani D, Fadelu T, Lin NU, Hassett M
Cell Systems
Sparse Dictionary Learning Recovers Pleiotropy from Human Cell Fitness Screens
Pan J, Kwon JJ, Talamas JA, Borah AA, Vazquez F, Boehm JS, Tsherniak A, Zitnik M, McFarland JM, Hahn WC
Clinical Cancer Research
Ricciuti B, Son J, Okoro JJ, Eum Y, Wang X, Paranal R, Lin M, Haikala HM, Li J, Alessi JV, Chhoeu C, Redig AJ, Köhler J, Dholakia KH, Gokhale PC, Awad MM, Jänne PA
Clinical Cancer Research
George S, Fletcher JA
Current Opinion in Endocrinology, Diabetes, and Obesity
Medical Management of Gastrointestinal Neuroendocrine Tumors
Perez K, Chan J
Developmental Cell
YAP1 and PRDM14 Converge to Promote Cell Survival and Tumorigenesis
Kim M, Ly SH, Xie Y, Duronio GN, Ford-Roshon D, Sulahian R, Rennhack JP, So J, Gjoerup O, Talamas JA, Grandclaudon M, Long HW, Doench JG, Sethi NS, Giannakis M, Hahn WC
Journal Adolescent and Young Adult Oncology
YAP1 and PRDM14 Converge to Promote Cell Survival and Tumorigenesis
Kim M, Ly SH, Xie Y, Duronio GN, Ford-Roshon D, Sulahian R, Rennhack JP, So J, Gjoerup O, Talamas JA, Grandclaudon M, Long HW, Doench JG, Sethi NS, Giannakis M, Hahn WC
Journal Adolescent and Young Adult Oncology
Chevalier LL, Michaud AL, Zhou ES, Chang G, Recklitis CJ
Journal of Cancer Survivorship
Cacciotti C, Chevalier LL, Medeiros-Nancarrow C, Recklitis C, Cooney TM
Journal of Child and Adolescent Trauma
Cleveland RW, Deming RS, Helton G, Wilson CR, Ullrich CK
Journal of Clinical Neuroscience
Agaronnik ND, Kwok A, Schoenfeld AJ, Lindvall C
JAMA Otolaryngology – Head and Neck Surgery
Shah H, Wang Y, Cheng SC, Gunasti L, Chen YH, Lako A, Guenette J, Rodig S, Jo VY, Uppaluri R, Haddad R, Schoenfeld JD, Jacene HA
Leukemia
Combination Therapy Targeting Erk1/2 and CDK4/6i in Relapsed Refractory Multiple Myeloma
Adamia S, Bhatt S, Wen K, Chyra Z, Fell GG, Tai YT, Pioso MS, Letai A, Dorfman DM, Hideshima T, Anderson KC
Leukemia
Yang J, Weisberg EL, Ni W, Meng C, Zhang S, Magin RS, Doherty L, Buhrlage SJ, Liu Griffin JD
Medical Physics
Huynh E, Boyle S, Campbell J, Penney J, Mak RH, Schoenfeld JD, Leeman JE, Williams CL
Pediatric Transplantation
Ma C, Al-Sayegh H, Shyr D, Lehmann LE, Chi SN
Prostate
Stover EH, Oh C, Keskula P, Choudhury AD, Tseng YY, Adalsteinsson VA, Lohr JG, Thorner AR, Ducar M, Kryukov GV, Rosenberg M, Freeman SS, Zhang Z, Wu X, Van Allen EM, Loda M, Wu CL, Taplin ME, Boehm JS
Science Advances
Interactions with Stromal Cells Promote a More Oxidized Cancer Cell Redox State in Pancreatic Tumors
Vander Heiden MG
Supportive Care in Cancer
Psychosocial Issues and Quality of Life of Parenting Partners of Young Women with Breast Cancer
Borstelmann NA, Gray TF, Gelber S, Rosenberg S, Zheng Y, Meyer M, Come S, Maramaldi P, Partridge AH
Trends in Cancer
Interplay between K-RAS and miRNAs
Shui B, Haigis KM