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.
November 1, 2021
Cancer Cell
Freed-Pastor WA, Eng G, Hwang WL, Schenkel JM, Deshpande V, Delorey T, Phillips D, Yilmaz OH, Regev A
The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T-cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
Cancer Discovery
Discovery and Features of an Alkylating Signature in Colorectal Cancer
Gurjao C, Zhong R, Haruki K, Li YY, Spurr LF, Reardon B, Ugai T, Zhang X, Cherniack AD, Song M, Van Allen EM, Meyerhardt JA, Nowak JA, Giovannucci EL, Wu K, Ogino S, Giannakis M
Several risk factors have been established for colorectal cancer, yet their direct mutagenic effects in patients' tumors remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 colorectal cancer cases that had occurred in three U.S.-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature that was previously undescribed in colorectal cancer and then showed the existence of a similar mutational process in normal colonic crypts. This alkylating signature is associated with high intakes of processed and unprocessed red meat prior to diagnosis. In addition, this signature was more abundant in the distal colorectum, predicted to target cancer driver mutations KRAS p.G12D, KRAS p.G13D, and PIK3CA p.E545K, and associated with poor survival. Together, these results link for the first time a colorectal mutational signature to a component of diet and further implicate the role of red meat in colorectal cancer initiation and progression.
SIGNIFICANCE: Colorectal cancer has several lifestyle risk factors, but the underlying mutations for most have not been observed directly in tumors. Analysis of 900 colorectal cancers with whole-exome sequencing and epidemiologic annotations revealed an alkylating mutational signature that was associated with red meat consumption and distal tumor location, as well as predicted to target KRAS p.G12D/p.G13D. This article is highlighted in the In This Issue feature, p. 2355.
Cancer Discovery
Cleary JM, Raghavan S, Wu Q, Li YY, Spurr LF, Gupta HV, Rubinson DA, Fetter IJ, Hornick JL, Nowak JA, Siravegna G, Goyal L, Shi L, Brais LK, Loftus M, Shinagare AB, Abrams TA, Clancy TE, Wang J, Patel AK, Sullivan RJ, Keller RB, Denning S, Hill ER, Shapiro GI, Ng K, Schrag D, Jänne PA, Hahn WC, Cherniack AD, Corcoran RB, Meyerson M, Bardeesy N, Wolpin BM
We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic.
SIGNIFICANCE: FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro, and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic.This article is highlighted in the In This Issue feature, p. 2355.
Cancer Discovery
Filho OM, Stein S, Trippa L, Spring LM, Waks AG, Wrabel E, DeMeo MK, Bardia A, King TA, Polyak K, Michor F, Winer EP, Krop IE
Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (ERBB2) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from two locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in >5% but <50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the nonheterogeneous subgroup and 0% in the heterogeneous group (P < 0.0001, adjusted for hormone receptor status). Single-cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 nonamplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies.
SIGNIFICANCE: HER2-targeted therapies improve cure rates in HER2-positive breast cancer, suggesting chemotherapy can be avoided in a subset of patients. We show that HER2 heterogeneity, particularly the fraction of ERBB2 nonamplified cancer cells, is a strong predictor of resistance to HER2 therapies and could potentially be used to optimize treatment selection. See related commentary by Okines and Turner, p. 2369. This article is highlighted in the In This Issue feature, p. 2355.
Cancer Discovery
Heckler M, Ali LR, Clancy-Thompson E, Qiang L, Ventre KS, Lenehan P, Roehle K, Luoma A, Boelaars K, Peters V, McCreary J, Boschert T, Wang ES, Suo S, Marangoni F, Mempel TR, Long HW, Wucherpfennig KW, Dougan M, Gray NS, Yuan GC, Tolaney SM, Dougan SK
CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity.
SIGNIFICANCE: CDK4/6 inhibition skews newly activated CD8+ T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8+ T-cell priming to tumor antigens prior to dosing with checkpoint blockade. This article is highlighted in the In This Issue feature, p. 2355.
Cancer Discovery
Togami K, Chung SS, Booth CAG, Kenyon CM, Cabal-Hierro L, Kim SS, Griffin GK, Ghandi M, Li YY, Lovitch SB, Louissaint A, Morgan EA, Weinstock DM, Lane AA
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDCs). BPDCN occurs at least three times more frequently in men than women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation.
Cell
Glimcher LH, Petsko GA
The 2021 Lasker Koshland Special Achievement Award will be presented to David Baltimore for an extraordinary career that has personified the combination of outstanding biomedical research and exemplary scientific statesmanship.
Cell
Wang X, Tokheim C, Gu SS, Wang B, Tang Q, Li Y, Traugh N, Zeng Z, Zhang Y, Li Z, Zhang B, Fu J, Xiao T, Li W, Meyer CA, Chu J, Jiang P, Cejas P, Lim K, Long H, Brown M, Liu XS
Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebp? protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebp?, which leads to polyubiquitination of C/ebp?. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebp? to suppress expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy in TNBC by regulating chemokine secretion and macrophage infiltration in the tumor microenvironment.
Journal of Clinical Oncology
Beyond the Front Line: Emerging Data for Maintenance Therapy in Pancreatic Cancer
Singh H, Perez K, Wolpin BM, Aguirre AJ
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
Journal of Clinical Oncology
Nab-Sirolimus for Patients with Malignant Perivascular Epithelioid Cell Tumors
Wagner AJ, Hornick JL, Du H, Kwiatkowski DJ
PURPOSE: Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor nab-sirolimus (AMPECT, NCT02494570).
PATIENTS AND METHODS: Patients with malignant PEComa were treated with nab-sirolimus 100 mg/m2 intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis.
RESULTS: Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a TSC2 mutation achieved a confirmed response versus 2 of 16 (13%) without TSC2 mutation (P < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade 4 treatment-related events occurred.
CONCLUSION: nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab-sirolimus represents an important new treatment option for this disease.
Journal of Clinical Oncology
Reply to G. R. Mohyuddin Et Al and A. Garfall Et Al
Richardson PG, Moreau P
We thank Mohyuddin et al and Garfall et al for their comments on our manuscript reporting the final overall survival (OS) analysis of the TOURMALINE-MM1 phase III trial and associated editorial. We agree that OS remains an important end point for patients and on the need for optimal sequencing of therapies. As demonstrated by the increasingly lengthy median OS in phase III trials in relapsed or refractory multiple myeloma, physicians are using the rapidly expanding range of treatments in combination or sequentially to substantially improve outcomes for patients. This is being done in the context of a highly heterogeneous disease and patient population, and with differing global access to novel therapies, requiring individualized treatment optimization and sequencing outside the clinical-trial setting. The result is an enormous and gratifying survival benefit for patients, inconceivable 20 years ago.
Journal of Clinical Oncology
Warren LEG, Bellon JR
We appreciate the interest expressed by Dr Wei and Dr Fang in our publication. Dr Wei and Dr Fang suggest that an analysis of variance statistical model should be used in the repeated-measures analysis of left ventricular ejection fraction (LVEF) over time in our population of patients with human epidermal growth factor receptor 2–positive metastatic breast cancer and CNS metastases treated with pertuzumab plus high-dose trastuzumab.
Journal of Clinical Oncology
Should Everyone with Ductal Carcinoma in Situ Receive Adjuvant Radiation?
Lin NU
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
Journal of the National Cancer Institute
Partridge AH
Cyclophosphamide is an important component of most adjuvant breast cancer chemotherapy regimens. However, research has repeatedly demonstrated that it also contributes substantially to the risk of gonadotoxicity in premenopausal women, an issue of great importance for young patients. The development of chemotherapy-induced premature ovarian insufficiency (POI) is associated with not only attendant infertility but also the additional negative health consequences of an early loss of ovarian function. Together with patient age, type, and dose of chemotherapy are the other crucial factors influencing gonadotoxicity risk, with alkylating agents such as cyclophosphamide being associated with the highest negative gonadal impact. Therefore, investigating the possibility of effective novel adjuvant chemotherapy regimens with lower risk of this long-term toxicity is a highly relevant clinical question.
Journal of the National Cancer Institute
Lipsyc-Sharf M, Ma C, McCleary NJ, Mayer RJ, Meyerhardt JA, Ng K
BACKGROUND: The incidence of young-onset colorectal cancer (yoCRC) is increasing. It is unknown if there are survival differences between young and older patients with metastatic colorectal cancer (mCRC).
METHODS:
We studied the association of age with survival in 2326 mCRC patients enrolled in the CALGB/SWOG 80405 trial, a multi-center, randomized trial of first-line chemotherapy plus biologics. The primary and secondary outcomes of this study were overall survival (OS) and progression-free survival (PFS), respectively, which were assessed by Kaplan Meier method and compared among younger versus older patients with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards modeling, adjusting for known prognostic variables. All statistical tests were 2-sided.RESULTS: Of 2326 eligible subjects, 514 (22.1%) were younger than age 50 years at study entry (yoCRC cohort). The median age of yoCRC patients was 44.3 vs. 62.5 years in patients age 50 and over. There was no statistically significant difference in OS between yoCRC vs. older-onset patients (median = 27.07 vs. 26.12 months; adjusted HR = 0.98, 95% CI = 0.88-1.10, P = .78). The median PFS was also similar in yoCRC vs. older patients (10.87 vs. 10.55‚Äâmonths) with an adjusted HR of 1.02 (95% CI = 0.92-1.13, P = .67). Patients younger than age 35 years had the shortest OS with median OS of 21.95 vs. 26.12 months in older-onset patients with an adjusted HR of 1.08 (95% CI = 0.81-1.44, Ptrend =0.93).
CONCLUSION: In this large study of mCRC patients, there were no statistically significant differences in survival between patients with yoCRC and CRC patients age 50 and older.
JAMA Oncology
Jänne PA
IMPORTANCE:Metastatic non-small cell lung cancer (mNSCLC) with EGFR exon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively target EGFRex20ins mutations.
OBJECTIVE:
To evaluate treatment outcomes and safety of mobocertinib in patients with previously treated EGFRex20ins-positive mNSCLC.DESIGN, SETTING, AND PARTICIPANTS: This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreated EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treated EGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort).
INTERVENTIONS: Mobocertinib 160 mg once daily.
MAIN OUTCOMES AND MEASURES:The primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety.
RESULTS:
Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash.CONCLUSIONS AND RELEVANCE: In this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treated EGFRex20ins-positive mNSCLC, with a manageable safety profile.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02716116.
Lancet Oncology
Davids MS, Lampson BL, Tyekucheva S, Wang Z, Lowney JC, Pazienza S, Montegaard J, Patterson V, Weinstock M, Crombie JL, Ng SY, Kim AI, Jacobson CA, LaCasce AS, Armand P, Arnason JE, Fisher DC, Brown JR
BACKGROUND:Both continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax-obinutuzumab are effective for previously untreated chronic lymphocytic leukaemia. We hypothesised that frontline time-limited, minimal residual disease (MRD)-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab would induce deep (ie, more patients with undetectable MRD) and durable remissions.
METHODS:
In this open-label, single-arm, investigator-sponsored, phase 2 study, patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma were recruited from two academic hospitals in Boston, MA, USA. Eligible patients were aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-2, and were treatment naive. Patients were treated in 28 day cycles. Acalabrutinib monotherapy was given orally at 100 mg twice daily for cycle 1, then combined for six cycles with intravenous obinutuzumab (100 mg on cycle 2 day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 and on day 1 of cycles 3-7); and from the beginning of cycle 4, oral venetoclax was dosed daily using an accelerated ramp-up from 20 mg on day 1 to 400 mg by day 22 and continued at this dose thereafter. Patients continued on acalabrutinib 100 mg twice daily and venetoclax 400 mg once daily until day 1 of cycle 16 or day 1 of cycle 25. If the patient had undetectable MRD in the bone marrow they were given the option to discontinue therapy at the start of cycle 16 (if also in complete remission) or at the start of cycle 25 (if at least in partial remission). The primary endpoint was complete remission with undetectable MRD in the bone marrow (defined asFINDINGS: Between Aug 2, 2018, and May 23, 2019, 37 patients with chronic lymphocytic leukaemia were enrolled and all received at least one dose of any study drug. The median age of patients was 63 years (IQR 57-70), and ten (27%) were female and 27 (73%) were male. Median follow-up was 27¬?6 months (IQR 25¬?1-28¬?2). At cycle 16 day 1, 14 (38% [95% CI 22-55]) of 37 participants had a complete remission with undetectable MRD in the bone marrow. The most common grade 3 or 4 haematological adverse event was neutropenia (16 [43%] of 37 patients). The most common grade 3-4 non-haematological adverse events were hyperglycaemia (three [8%]) and hypophosphataemia (three [8%]). Serious adverse events occurred in nine (24%) patients; the most common was neutropenia in three (8%) patients. There have been no deaths on study.
INTERPRETATION: Acalabrutinib, venetoclax, and obinutuzumab is a highly active and well tolerated frontline therapy for chronic lymphocytic leukaemia. Although the primary endpoint of this study was not met, the high proportion of patients who had undetectable MRD in the bone marrow supports further investigation of this regimen, which is being tested against acalabrutinib-venetoclax and chemoimmunotherapy in an ongoing phase 3 study (NCT03836261).
FUNDING:AstraZeneca and a Dana-Farber Cancer Institute Collaborative Award.
Lancet Oncology
Leveraging External Data in the Design and Analysis of Clinical Trials in Neuro-Oncology
Rahman R, Ventz S, Wen PY, Alexander BM, Trippa L
Integration of external control data, with patient-level information, in clinical trials has the potential to accelerate the development of new treatments in neuro-oncology by contextualising single-arm studies and improving decision making (eg, early stopping decisions). Based on a series of presentations at the 2020 Clinical Trials Think Tank hosted by the Society of Neuro-Oncology, we provide an overview on the use of external control data representative of the standard of care in the design and analysis of clinical trials. High-quality patient-level records, rigorous methods, and validation analyses are necessary to effectively leverage external data. We review study designs, statistical methods, risks, and potential distortions in using external data from completed trials and real-world data, as well as data sources, data sharing models, ongoing work, and applications in glioblastoma.
Nature
A Neuroanatomical Basis for Electroacupuncture to Drive the Vagal-Adrenal Axis
Liu S, Wang Z, Su Y, Qi L, Yang W, Fu M, Ma Q
Somatosensory autonomic reflexes allow electroacupuncture stimulation (ES) to modulate body physiology at distant sites1-6 (for example suppressing severe systemic inflammation6-9). Since the 1970s, an emerging organizational rule about these reflexes has been the presence of body-region specificity. For example, ES at the hindlimb ST36 acupoint but not the abdominal ST25 acupoint can drive the vagal-adrenal anti-inflammatory axis in mice. The neuroanatomical basis of this somatotopic organization is, however, unknown. Here we show that PROKR2Cre-marked sensory neurons, which innervate the deep hindlimb fascia (for example, the periosteum) but not abdominal fascia (for example, the peritoneum), are crucial for driving the vagal-adrenal axis. Low-intensity ES at the ST36 site in mice with ablated PROKR2Cre-marked sensory neurons failed to activate hindbrain vagal efferent neurons or to drive catecholamine release from adrenal glands. As a result, ES no longer suppressed systemic inflammation induced by bacterial endotoxins. By contrast, spinal sympathetic reflexes evoked by high-intensity ES at both ST25 and ST36 sites were unaffected. We also show that optogenetic stimulation of PROKR2Cre-marked nerve terminals through the ST36 site is sufficient to drive the vagal-adrenal axis but not sympathetic reflexes. Furthermore, the distribution patterns of PROKR2Cre nerve fibres can retrospectively predict body regions at which low-intensity ES will or will not effectively produce anti-inflammatory effects. Our studies provide a neuroanatomical basis for the selectivity and specificity of acupoints in driving specific autonomic pathways.
Nature
Biologically Informed Deep Neural Network for Prostate Cancer Discovery
Elmarakeby HA, Arafeh R, Crowdis J, Gang S, Liu D, AlDubayan SH, Salari K, Richter C, Arnoff TE, Park J, Hahn WC, Van Allen EM
The determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer remains a major biological and clinical challenge. Recent advances in interpretability of machine learning models as applied to biomedical problems may enable discovery and prediction in clinical cancer genomics. Here we developed P-NET-a biologically informed deep learning model-to stratify patients with prostate cancer by treatment-resistance state and evaluate molecular drivers of treatment resistance for therapeutic targeting through complete model interpretability. We demonstrate that P-NET can predict cancer state using molecular data with a performance that is superior to other modelling approaches. Moreover, the biological interpretability within P-NET revealed established and novel molecularly altered candidates, such as MDM4 and FGFR1, which were implicated in predicting advanced disease and validated in vitro. Broadly, biologically informed fully interpretable neural networks enable preclinical discovery and clinical prediction in prostate cancer and may have general applicability across cancer types.
Nature Communications
Subtype Heterogeneity and Epigenetic Convergence in Neuroendocrine Prostate Cancer
Cejas P, Xie Y, Font-Tello A, Lim K, Syamala S, Qiu X, Tewari AK, Shah N, Ellis L, Alaiwi SA, Seo JH, Baca S, Beltran H, Pomerantz M, Crowdis J, Van Allen EM, Bellmunt J, DeCaprio J, Farago A, Dyson N, Liu XS, Freedman M, Brown M, Long HW
Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes of a range of human NECs and show convergence to the activation of a common epigenetic program. With a particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), we analyze cell lines, patient-derived xenograft (PDX) models and human clinical samples to show the existence of two distinct NEPC subtypes based on the expression of the neuronal transcription factors ASCL1 and NEUROD1. While in cell lines and PDX models these subtypes are mutually exclusive, single-cell analysis of human clinical samples exhibits a more complex tumor structure with subtypes coexisting as separate sub-populations within the same tumor. These tumor sub-populations differ genetically and epigenetically contributing to intra- and inter-tumoral heterogeneity in human metastases. Overall, our results provide a deeper understanding of the shared clinicopathological characteristics shown by NECs. Furthermore, the intratumoral heterogeneity of human NEPCs suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy.
Nature Communications
Whole Chromosome Loss and Genomic Instability in Mouse Embryos After CRISPR-Cas9 Genome Editing
Papathanasiou S, Blaine LJ, Leibowitz ML, Zhang CZ, Pellman D
Karyotype alterations have emerged as on-target complications from CRISPR-Cas9 genome editing. However, the events that lead to these karyotypic changes in embryos after Cas9-treatment remain unknown. Here, using imaging and single-cell genome sequencing of 8-cell stage embryos, we track both spontaneous and Cas9-induced karyotype aberrations through the first three divisions of embryonic development. We observe the generation of abnormal structures of the nucleus that arise as a consequence of errors in mitosis, including micronuclei and chromosome bridges, and determine their contribution to common karyotype aberrations including whole chromosome loss that has been recently reported after editing in embryos. Together, these data demonstrate that Cas9-mediated germline genome editing can lead to unwanted on-target side effects, including major chromosome structural alterations that can be propagated over several divisions of embryonic development.
Nature Medicine
Choueiri TK, McDermott DF, Michaelson MD
Hypoxia-inducible factor-2? (HIF-2?) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2?. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ?3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2? inhibition might offer an effective treatment for ccRCC.
Nature Methods
Systematic Investigation of Cytokine Signaling Activity at the Tissue and Single-Cell Levels
CWucherpfennig KW
Cytokines are critical for intercellular communication in human health and disease, but the investigation of cytokine signaling activity has remained challenging due to the short half-lives of cytokines and the complexity/redundancy of cytokine functions. To address these challenges, we developed the Cytokine Signaling Analyzer (CytoSig;https://cytosig.ccr.cancer.gov), providing both a database of target genes modulated by cytokines and a predictive model of cytokine signaling cascades from transcriptomic profiles. We collected 20,591 transcriptome profiles for human cytokine, chemokine and growth factor responses. This atlas of transcriptional patterns induced by cytokines enabled the reliable prediction of signaling activities in distinct cell populations in infectious diseases, chronic inflammation and cancer using bulk and single-cell transcriptomic data. CytoSig revealed previously unidentified roles of many cytokines, such as BMP6 as an anti-inflammatory factor, and identified candidate therapeutic targets in human inflammatory diseases, such as CXCL8 for severe coronavirus disease 2019.
Proceedings of the National Academy of Sciences of the U.S.A.
He Y, Diossy M, Bowman-Colin C, Reed R, Jennings R, Novak J, Cohen EF, Giobbie-Hurder A, Bronson RT, Signoretti S, Szallasi Z, Livingston DM
BRCA1 germline mutations are associated with an increased risk of breast and ovarian cancer. Recent findings of others suggest that BRCA1 mutation carriers also bear an increased risk of esophageal and gastric cancer. Here, we employ a Brca1/Trp53 mouse model to show that unresolved replication stress (RS) in BRCA1 heterozygous cells drives esophageal tumorigenesis in a model of the human equivalent. This model employs 4-nitroquinoline-1-oxide (4NQO) as an RS-inducing agent. Upon drinking 4NQO-containing water, Brca1 heterozygous mice formed squamous cell carcinomas of the distal esophagus and forestomach at a much higher frequency and speed (?90 to 120 d) than did wild-type (WT) mice, which remained largely tumor free. Their esophageal tissue, but not that of WT control mice, revealed evidence of overt RS as reflected by intracellular CHK1 phosphorylation and 53BP1 staining. These Brca1 mutant tumors also revealed higher genome mutation rates than those of control animals; the mutational signature SBS4, which is associated with tobacco-induced tumorigenesis; and a loss of Brca1 heterozygosity (LOH). This uniquely accelerated Brca1 tumor model is also relevant to human esophageal squamous cell carcinoma, an often lethal tumor.
AJR American Journal of Roentgenology
Intercostal Brown Adipose Tissue on FDG PET/CT
Dabiri BE, Jacene HA
Allergy
Uchida AM, Lenehan PJ, Vimalathas P, Miller KC, Valencia-Yang M, Qiang L, Canha LA, Ali LR, Dougan M, Garber JJ, Dougan SK
American Journal of Hematology
Castillo JJ, Lamacchia J, Flynn CA, Sarosiek S
American Journal of Hematology
Zhu H, Ficarro SB, Alexander WM, Fleming LE, Adelmant G, Marto JA
Annals of Surgical Oncology
Arm Morbidity After Local Therapy for Young Breast Cancer Patients
Kuijer A, Dominici LS, Rosenberg SM, Hu J, Gelber S, Di Lascio S, Wong JS, Come SE, Sprunck-Harrild K, Partridge AH, King TA
Bioinformatics
New Strategies to Improve Minimap2 Alignment Accuracy
Li H
Blood Advances
Garcia JS, Kim HT, Murdock HM, Cutler CS, Brock J, Gooptu M, Ho VT, Koreth J, Nikiforow S, Romee R, Shapiro RM, Loschi F, Ryan JA, Fell G, Karp HQ, Lucas F, Kim AS, Potter DS, Mashaka T, Stone RM, DeAngelo DJ, Letai A, Lindsley RC, Soiffer RJ, Antin JH