Publications by authors named "Zvi Fuks"

90 Publications

Colorectal Cancer Develops Inherent Radiosensitivity That Can Be Predicted Using Patient-Derived Organoids.

Cancer Res 2022 Jun;82(12):2298-2312

Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York.

Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here, we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDO) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically expanded Lgr5+ intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination-mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses.

Significance: Analysis of inherent tissue radiosensitivity of patient-derived organoids may provide a readout predictive of neoadjuvant therapy response to radiation in rectal cancer, potentially allowing pretreatment stratification of patients likely to benefit from this approach.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-4128DOI Listing
June 2022

Urethra Sparing With Target Motion Mitigation in Dose-Escalated Extreme Hypofractionated Prostate Cancer Radiotherapy: 7-Year Results From a Phase II Study.

Front Oncol 2022 29;12:863655. Epub 2022 Mar 29.

Department of Radiation Oncology, Champalimaud Centre for the Unknown, Lisbon, Portugal.

Purpose: To explore whether the rectal distension-mediated technique, harnessing human physiology to achieve intrafractional prostate motion mitigation, enables urethra sparing by inverse dose painting, thus promoting dose escalation with extreme hypofractionated stereotactic ablative radiotherapy (SABR) in prostate cancer.

Materials And Methods: Between June 2013 and December 2018, 444 patients received 5 × 9 Gy SABR over 5 consecutive days. Rectal distension-mediated SABR was employed insertion of a 150-cm air-inflated endorectal balloon. A Foley catheter loaded with 3 beacon transponders was used for urethra visualization and online tracking. MRI-based planning using Volumetric Modulated Arc Therapy - Image Guided Radiotherapy (VMAT-IGRT) with inverse dose painting was employed in delivering the planning target volume (PTV) dose and in sculpting exposure of organs at risk (OARs). A 2-mm margin was used for PTV expansion, reduced to 0 mm at the interface with critical OARs. All plans fulfilled D ≥45 Gy. Target motion ≥2 mm/5 s motions mandated treatment interruption and target realignment prior to completion of the planned dose delivery.

Results: Patient compliance to the rectal distension-mediated immobilization protocol was excellent, achieving reproducible daily prostate localization at a patient-specific retropubic niche. Online tracking recorded ≤1-mm intrafractional target deviations in 95% of treatment sessions, while target realignment in ≥2-mm deviations enabled treatment completion as scheduled in all cases. The cumulative incidence rates of late grade ≥2 genitourinary (GU) and gastrointestinal (GI) toxicities were 5.3% and 1.1%, respectively. The favorable toxicity profile was corroborated by patient-reported quality of life (QOL) outcomes. Median prostate-specific antigen (PSA) nadir by 5 years was 0.19 ng/ml. The cumulative incidence rate of biochemical failure using the Phoenix definition was 2%, 16.6%, and 27.2% for the combined low/favorable-intermediate, unfavorable intermediate, and high-risk categories, respectively. Patients with a PSA failure underwent a Ga-labeled prostate-specific membrane antigen (Ga-PSMA) scan showing a 20.2% cumulative incidence of intraprostatic relapses in biopsy International Society of Urological Pathology (ISUP) grade ≥3.

Conclusion: The rectal distension-mediated technique is feasible and well tolerated. Dose escalation to 45 Gy with urethra-sparing results in excellent toxicity profiles and PSA relapse rates similar to those reported by other dose-escalated regimens. The existence of intraprostatic recurrences in patients with high-risk features confirms the notion of a high α/β ratio in these phenotypes resulting in diminished effectiveness with hypofractionated dose escalation.
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http://dx.doi.org/10.3389/fonc.2022.863655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012148PMC
March 2022

Disruption of the crypt niche promotes outgrowth of mutated colorectal tumor stem cells.

JCI Insight 2022 03 8;7(5). Epub 2022 Mar 8.

Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Recent data establish a logarithmic expansion of leucine rich repeat containing G protein coupled receptor 5-positive (Lgr5+) colonic epithelial stem cells (CESCs) in human colorectal cancer (CRC). Complementary studies using the murine 2-stage azoxymethane-dextran sulfate sodium (AOM-DSS) colitis-associated tumor model indicate early acquisition of Wnt pathway mutations drives CESC expansion during adenoma progression. Here, subdivision of the AOM-DSS model into in vivo and in vitro stages revealed DSS induced physical separation of CESCs from stem cell niche cells and basal lamina, a source of Wnt signals, within hours, disabling the stem cell program. While AOM delivery in vivo under non-adenoma-forming conditions yielded phenotypically normal mucosa and organoids derived thereof, niche injury ex vivo by progressive DSS dose escalation facilitated outgrowth of Wnt-independent dysplastic organoids. These organoids contained 10-fold increased Lgr5+ CESCs with gain-of-function Wnt mutations orthologous to human CRC driver mutations. We posit CRC originates by niche injury-induced outgrowth of normally suppressed mutated stem cells, consistent with models of adaptive oncogenesis.
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http://dx.doi.org/10.1172/jci.insight.153793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983138PMC
March 2022

Early PSA density kinetics predicts biochemical and local failure following extreme hypofractionated radiotherapy in intermediate-risk prostate cancer.

Radiother Oncol 2022 04 18;169:35-42. Epub 2022 Feb 18.

The Champalimaud Centre for the Unknown, Lisbon, Portugal; Memorial Sloan Kettering Cancer Center, New York, USA.

Purpose: The present study explores PSA density (PSA-D) as predictor of biochemical and local failure in organ-confined prostate cancer at 3-6 months after hypofractionated stereotactic ablative radiotherapy (SABR).

Methods And Materials: A cohort of 219, hormone-naïve, NCCN intermediate-risk prostate cancer patients were derived from a phase 2 study of 5 × 9 Gy prostate cancer SABR. PSA-D was calculated at 3 and 6 months by dividing serum PSA by the MR-derived prostate CTV, while the slope of the 3-6 months curve was used to express the kinetics of PSA-D decay.

Results: The median follow-up was 60.3 (range 46-76) months, and the actuarial 7-year bRFS was 98.0% for intermediate-risk favorable (FIR) patients versus 84.5% for the unfavorable (UIR) subgroup (P = 0.02). Fourteen patients developed a Phoenix-defined biochemical PSA relapse (bRFS) at a median of 34.2 months, 11 confirmed with Ga-PSMA PET/CT scan that revealed tracer uptake at the site of dominant intraprostatic pretreatment lesion in 8 patients. The 3-month PSA-D concertation (cut-off 0.08 ng/ml) and 3-6 months decay slope (cut-off -0.45) values were predictive of long-term bRFS. A dual adverse PSA-D permutation was detected in 25/148 UIR patients, exhibiting 47.5% 7-year bRFS compared with 94.1% for the remaining 123 UIR patients with favorable PSA-D kinetics (P = 0.0006). Intraprostatic local relapse in patients with a 3-month PSA-D > 0.080 ng/ml was 11.0% vs. 1.7% for patients with PSA-D ≤ 0.080 ng/ml (P = 0.01) and 2.3% vs. 4.3%, respectively, for nodal progression (P = 0.68).

Conclusions: Early post-treatment PSA-D kinetics transcends pre-treatment risk stratification of tumor relapse and adds a nuance in the biological characterization of intermediate-risk prostate cancer phenotypes. The dual adverse PSA-D algorithm may serve as a tool to validate current search of classifiers of radioresistance in prostate cancer with therapeutic implications.
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http://dx.doi.org/10.1016/j.radonc.2022.02.016DOI Listing
April 2022

Positron Emission Tomography-Derived Metrics Predict the Probability of Local Relapse After Oligometastasis-Directed Ablative Radiation Therapy.

Adv Radiat Oncol 2022 Mar-Apr;7(2):100864. Epub 2021 Dec 5.

Department of Radiation Oncology, Champalimaud Centre for the Unknown, Lisbon, Portugal.

Purpose: Early positron emission tomography-derived metrics post-oligometastasis radioablation may predict impending local relapses (LRs), providing a basis for a timely ablation.

Methods And Materials: Positron emission tomography data of 623 lesions treated with either 24 Gy single-dose radiation therapy (SDRT) (n = 475) or 3 ×  9 Gy stereotactic body radiation therapy (SBRT) (n = 148) were analyzed in a training data set (n = 246) to obtain optimal cutoffs for pretreatment maximum standardized uptake value (SUV) and its 3-month posttreatment decline (ΔSUV) in predicting LR risk, validated in a data set unseen to testing (n = 377).

Results: At a median of 21.7 months, 91 lesions developed LRs: 39 of 475 (8.2%) after SDRT and 52 of 148 (35.1%) after SBRT. The optimal cutoff values were 12 for SUV and -75% for ΔSUV. Bivariate SUV/ΔSUV permutations rendered a 3-tiered LR risk stratification of dual-favorable (low risk), 1 adverse (intermediate risk) and dual-adverse (high risk). Actuarial 5-year local relapse-free survival rates were 93.9% versus 89.6% versus 57.1% ( < .0001) and 76.1% versus 48.3% versus 8.2% ( < .0001) for SDRT and SBRT, respectively. The SBRT area under the ROC curve was 0.71 (95% CI, 0.61-0.79) and the high-risk subgroup yielded a 76.5% true positive LR prediction rate.

Conclusions: The SBRT dual-adverse SUV/ΔSUV category LR prediction power provides a basis for prospective studies testing whether a timely ablation of impending LRs affects oligometastasis outcomes.
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http://dx.doi.org/10.1016/j.adro.2021.100864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752878PMC
December 2021

Single-Dose Radiotherapy for Prostate Cancer-Lessons Learned From Single-Fraction High-Dose-Rate Brachytherapy-Reply.

JAMA Oncol 2021 10;7(10):1573

Champalimaud Centre for the Unknown, Lisbon, Portugal.

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http://dx.doi.org/10.1001/jamaoncol.2021.2694DOI Listing
October 2021

In Reply to Rans et al.

Int J Radiat Oncol Biol Phys 2021 07;110(3):911-912

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1016/j.ijrobp.2021.02.040DOI Listing
July 2021

Reproducibility and accuracy of a target motion mitigation technique for dose-escalated prostate stereotactic body radiotherapy.

Radiother Oncol 2021 07 13;160:240-249. Epub 2021 May 13.

The Champalimaud Centre for the Unknown, Lisbon, Portugal; Memorial Sloan Kettering Cancer Center, New York, USA.

Background And Purpose: To quantitate the accuracy, reproducibility and prostate motion mitigation efficacy rendered by a target immobilization method used in an intermediate-risk prostate cancer dose-escalated 5×9Gy SBRT study.

Material And Methods: An air-inflated (150 cm) endorectal balloon and Foley catheter with three electromagnetic beacon transponders (EBT) were used to mitigate and track intra-fractional target motion. A 2 mm margin was used for PTV expansion, reduced to 0 mm at the interface with critical OARs. EBT-detected ≥ 2 mm/5 s motions mandated treatment interruption and target realignment prior to completion of planned dose delivery. Geometrical uncertainties were measured with an in-house ESAPI script.

Results: Quantitative data were obtained in 886 sessions from 189 patients. Mean PTV dose was 45.8 ± 0.4 Gy (D95 = 40.5 ± 0.4 Gy). A mean of 3.7 ± 1.7 CBCTs were acquired to reach reference position. Mean treatment time was 19.5 ± 12 min, 14.1 ± 11 and 5.4 ± 5.9 min for preparation and treatment delivery, respectively. Target motion of 0, 1-2 and >2 mm/10 min were observed in 59%, 30% and 11% of sessions, respectively. Temporary beam-on hold occurred in 7.4% of sessions, while in 6% a new reference CBCT was required to correct deviations. Hence, all sessions were completed with application of the planned dose. Treatment preparation time > 15 min was significantly associated with the need of a second reference CBCT. Overall systematic and random geometrical errors were in the order of 1 mm.

Conclusion: The prostate immobilization technique explored here affords excellent accuracy and reproducibility, enabling normal tissue dose sculpting with tight PTV margins.
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http://dx.doi.org/10.1016/j.radonc.2021.05.004DOI Listing
July 2021

Disabling the Fanconi Anemia Pathway in Stem Cells Leads to Radioresistance and Genomic Instability.

Cancer Res 2021 07 3;81(13):3706-3716. Epub 2021 May 3.

Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York.

Fanconi anemia is an inherited genome instability syndrome characterized by interstrand cross-link hypersensitivity, congenital defects, bone marrow failure, and cancer predisposition. Although DNA repair mediated by Fanconi anemia genes has been extensively studied, how inactivation of these genes leads to specific cellular phenotypic consequences associated with Fanconi anemia is not well understood. Here we report that Fanconi anemia stem cells in the germline and in murine embryos display marked nonhomologous end joining (NHEJ)-dependent radiation resistance, leading to survival of progeny cells carrying genetic lesions. In contrast, DNA cross-linking does not induce generational genomic instability in Fanconi anemia stem cells, as widely accepted, but rather drives NHEJ-dependent apoptosis in both species. These findings suggest that Fanconi anemia is a stem cell disease reflecting inappropriate NHEJ, which is mutagenic and carcinogenic as a result of DNA misrepair, while marrow failure represents hematopoietic stem cell apoptosis. SIGNIFICANCE: This study finds that Fanconi anemia stem cells preferentially activate error-prone NHEJ-dependent DNA repair to survive irradiation, thereby conferring generational genomic instability that is instrumental in carcinogenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445591PMC
July 2021

Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair.

JCI Insight 2021 04 22;6(8). Epub 2021 Apr 22.

Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

After 9/11, threat of nuclear attack on American urban centers prompted government agencies to develop medical radiation countermeasures to mitigate hematopoietic acute radiation syndrome (H-ARS) and higher-dose gastrointestinal acute radiation syndrome (GI-ARS) lethality. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS in preclinical models, no mitigator potentially deliverable under mass casualty conditions preserves GI tract. Here, we report generation of an anti-ceramide 6B5 single-chain variable fragment (scFv) and show that s.c. 6B5 scFv delivery at 24 hours after a 90% lethal GI-ARS dose of 15 Gy mitigated mouse lethality, despite administration after DNA repair was complete. We defined an alternate target to DNA repair, an evolving pattern of ceramide-mediated endothelial apoptosis after radiation, which when disrupted by 6B5 scFv, initiates a durable program of tissue repair, permitting crypt, organ, and mouse survival. We posit that successful preclinical development will render anti-ceramide 6B5 scFv a candidate for inclusion in the Strategic National Stockpile for distribution after a radiation catastrophe.
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http://dx.doi.org/10.1172/jci.insight.145380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119204PMC
April 2021

Safety and Efficacy of Virtual Prostatectomy With Single-Dose Radiotherapy in Patients With Intermediate-Risk Prostate Cancer: Results From the PROSINT Phase 2 Randomized Clinical Trial.

JAMA Oncol 2021 May;7(5):700-708

The Champalimaud Centre for the Unknown, Lisbon, Portugal.

Importance: Ultra-high single-dose radiotherapy (SDRT) represents a potential alternative to curative extreme hypofractionated stereotactic body radiotherapy (SBRT) in organ-confined prostate cancer.

Objective: To compare toxic effect profiles, prostate-specific antigen (PSA) responses, and quality-of-life end points of SDRT vs extreme hypofractionated SBRT.

Design, Setting, And Participants: The PROSINT single-institution phase 2 randomized clinical trial accrued, between September 2015 and January 2017, 30 participants with intermediate-risk prostate cancer to receive SDRT or extreme hypofractionated SBRT. Androgen deprivation therapy was not permitted. Data were analyzed from March to May 2020.

Interventions: Patients were randomized in a 1:1 ratio to receive 5 × 9 Gy SBRT (control arm) or 24 Gy SDRT (test arm).

Main Outcomes And Measures: The primary end point was toxic effects; the secondary end points were PSA response, PSA relapse-free survival, and patient-reported quality of life measured with the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaires.

Results: A total of 30 men were randomized; median (interquartile range) age was 66.3 (61.2-69.9) and 73.6 (64.7-75.9) years for the SBRT and SDRT arms, respectively. Time to appearance and duration of acute and late toxic effects were similar in the 2 trial arms. Cumulative late actuarial urinary toxic effects did not differ for grade 1 (hazard ratio [HR], 0.41; 90% CI, 0.13-1.27) and grade 2 or greater (HR, 1.07; 90% CI, 0.21-5.57). Actuarial grade 1 late gastrointestinal (GI) toxic effects were comparable (HR, 0.37; 90% CI, 0.07-1.94) and there were no grade 2 or greater late GI toxic effects. Declines in PSA level to less than 0.5 ng/mL occurred by 36 months in both study arms. No PSA relapses occurred in favorable intermediate-risk disease, while in the unfavorable category, the actuarial 4-year PSA relapse-free survival values were 75.0% vs 64.0% (HR, 0.76; 90% CI, 0.17-3.31) for SBRT vs SDRT, respectively. The EPIC-26 median summary scores for the genitourinary and GI domains dropped transiently at 1 month and returned to pretreatment scores by 3 months in both arms. The IPSS-derived transient late urinary flare symptoms occurred at 9 to 18 months in 20% (90% CI, 3%-37%) of patients receiving SDRT.

Conclusions And Relevance: In this randomized clinical trial among patients with intermediate-risk prostate cancer, SDRT was safe and associated with low toxicity, and the tumor control and quality-of-life end points closely match the SBRT arm outcomes. Further studies are encouraged to explore indications for SDRT in the cure of prostate cancer.

Trial Registration: ClinicalTrials.gov Identifier: NCT02570919.
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http://dx.doi.org/10.1001/jamaoncol.2021.0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953338PMC
May 2021

Phase 3 Multi-Center, Prospective, Randomized Trial Comparing Single-Dose 24 Gy Radiation Therapy to a 3-Fraction SBRT Regimen in the Treatment of Oligometastatic Cancer.

Int J Radiat Oncol Biol Phys 2021 07 8;110(3):672-679. Epub 2021 Jan 8.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: This prospective phase 3 randomized trial was designed to test whether ultra high single-dose radiation therapy (24 Gy SDRT) improves local control of oligometastatic lesions compared to a standard hypofractionated stereotactic body radiation therapy regimen (3 × 9 Gy SBRT). The secondary endpoint was to assess the associated toxicity and the impact of ablation on clinical patterns of metastatic progression.

Methods And Materials: Between November 2010 and September 2015, 117 patients with 154 oligometastatic lesions (≤5/patient) were randomized in a 1:1 ratio to receive 24 Gy SDRT or 3 × 9 Gy SBRT. Local control within the irradiated field and the state of metastatic spread were assessed by periodic whole-body positron emission tomography/computed tomography and/or magnetic resonance imaging. Median follow-up was 52 months.

Results: A total of 59 patients with 77 lesions were randomized to 24 Gy SDRT and 58 patients with 77 lesions to 3 × 9 Gy SBRT. The cumulative incidence of local recurrence for SDRT-treated lesions was 2.7% (95% confidence interval [CI], 0%-6.5%) and 5.8% (95% CI, 0.2%-11.5%) at years 2 and 3, respectively, compared with 9.1% (95% CI, 2.6%-15.6%) and 22% (95% CI, 11.9%-32.1%) for SBRT-treated lesions (P = .0048). The 2- and 3-year cumulative incidences of distant metastatic progression in the SDRT patients were 5.3% (95% CI, 0%-11.1%), compared with 10.7% (95% CI, 2.5%-18.8%) and 22.5% (95% CI, 11.1%-33.9%), respectively, for the SBRT patients (P = .010). No differences in toxicity were observed.

Conclusions: The study confirms SDRT as a superior ablative treatment, indicating that effective ablation of oligometastatic lesions is associated with significant mitigation of distant metastatic progression.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.004DOI Listing
July 2021

Conformal Avoidance of Normal Organs at Risk by Perfusion-Modulated Dose Sculpting in Tumor Single-Dose Radiation Therapy.

Int J Radiat Oncol Biol Phys 2021 01 7;109(1):288-297. Epub 2020 Aug 7.

The Champalimaud Centre for the Unknown, Lisbon, Portugal; Memorial Sloan Kettering Cancer Center, New York City, New York.

Purpose: Although 24 Gy single-dose radiation therapy (SDRT) renders >90% 5-year local relapse-free survival in human solid tumor lesions, SDRT delivery is not feasible in ∼50% of oligometastatic lesions owing to interference by dose/volume constraints of a serial organ at risk (OAR). Conformal OAR avoidance is based on a hypothetical model positing that the recently described SDRT biology specifically permits volumetric subdivision of the SDRT dose, such that high-intensity vascular drivers of SDRT lethality, generated within a major tumor subvolume exposed to a high 24 Gy dose (high-dose planning target volume [PTV), would equilibrate SDRT signaling intensity throughout the tumor interstitial space, rendering bystander radiosensitization of a minor subvolume (perfusion-modulated dose sculpting PTV [PTV]), dose-sculpted to meet a serial OAR dose/volume constraint. An engineered PTV may thus yield tumor ablation despite PMDS dose reduction and conformally avoiding OAR exposure to a toxic dose.

Methods And Materials: Dose fall-off within the PTV penumbra of oligometastatic lesions was planned and delivered by intensity modulated inverse dose painting. SDRT- and SDRT-PMDS-treated lesions were followed with periodic positron emission tomography/computed tomography imaging to assess local tumor control.

Results: Cumulative baseline 5-year local relapse rates of oligometastases treated with 24 Gy SDRT alone (8% relapses, n = 292) were similar in moderate PTV dose-sculpted (23-18 Gy, n = 76, 11% relapses, P = .36) and extreme dose-sculpted (<18 Gy, n = 61, 14% relapses, P = .29) lesions, provided the major 24 Gy PTV constituted ≥60% of the total PTV. In contrast, 28% of local relapses occurred in 26 extreme dose-sculpted PTV lesions when PTV constituted <60% of the total PTV (P = .004), suggesting a threshold for the PTV bystander effect.

Conclusion: The study provides compelling clinical support for the bystander radiosensitization hypothesis, rendering local cure of tumor lesions despite a ≥25% PTV dose reduction of the 24 Gy PTV dose, adapted to conformally meet OAR dose/volume constraints. The SDRT-PMDS approach thus provides a therapeutic resolution to otherwise radioablation-intractable oligometastatic disease.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456416PMC
January 2021

Enhancement of Soft Tissue Sarcoma Response to Gemcitabine through Timed Administration of a Short-Acting Anti-Angiogenic Agent.

Cell Physiol Biochem 2020 Jul;54(4):707-718

Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, NY, USA,

Background/aims: Despite enormous effort, anti-angiogenic drugs have not lived up to the promise of globally-enhancing anti-cancer therapies. Clinically, anti-angiogenic drugs have been used to persistently suppress vascular endothelial growth factor (VEGF) in order to "normalize" dysfunctional neo-angiogenic microvasculature and prevent recruitment of endothelial progenitors. Recently, we showed that a 1h pre-treatment with anti-angiogenic drugs prior to ultra-high single dose radiotherapy and specific chemotherapies transiently de-represses acid sphingomyelinase (ASMase), leading to enhanced cancer therapy-induced, ceramide-mediated vascular injury and tumor response. Here we formally decipher parameters of chemotherapy induction of endothelial sphingolipid signaling events and define principles for optimizing anti-angiogenic chemosensitization.

Methods: These studies examine the antimetabolite chemotherapeutic gemcitabine in soft tissue sarcoma (STS), a clinically-relevant combination.

Results: Initial studies address the theoretic problem that anti-angiogenic drugs such as bevacizumab, an IgG with a 3-week half-life, have the potential for accumulating during the 3-week chemotherapeutic cycles currently standard-of-care for STS treatment. We show that anti-angiogenic ASMase-dependent enhancement of the response of MCA/129 fibrosarcomas in sv129/BL6 mice to gemcitabine progressively diminishes as the level of the VEGFR2 inhibitor DC101, an IgG, accumulates, suggesting a short-acting anti-angiogenic drug might be preferable in multi-cycle chemotherapeutic regimens. Further, we show lenvatinib, a VEGFR2 tyrosine kinase inhibitor with a short half-life, to be superior to DC101, enhancing gemcitabine-induced endothelial cell apoptosis and tumor response in a multi-cycle treatment schedule.

Conclusion: We posit that a single delivery of a short-acting anti-angiogenic agent at 1h preceding each dose of gemcitabine and other chemotherapies may be more efficacious for repeated sensitization of the ASMase pathway in multi-cycle chemotherapy regimens than current treatment strategies.
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http://dx.doi.org/10.33594/000000250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567213PMC
July 2020

Fusion of lysosomes to plasma membrane initiates radiation-induced apoptosis.

J Cell Biol 2020 04;219(4)

Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY.

Diverse stresses, including reactive oxygen species (ROS), ionizing radiation, and chemotherapies, activate acid sphingomyelinase (ASMase) and generate the second messenger ceramide at plasma membranes, triggering apoptosis in specific cells, such as hematopoietic cells and endothelium. Ceramide elevation drives local bilayer reorganization into ceramide-rich platforms, macrodomains (0.5-5-µm diameter) that transmit apoptotic signals. An unresolved issue is how ASMase residing within lysosomes is released extracellularly within seconds to hydrolyze sphingomyelin preferentially enriched in outer plasma membranes. Here we show that physical damage by ionizing radiation and ROS induces full-thickness membrane disruption that allows local calcium influx, membrane lysosome fusion, and ASMase release. Further, electron microscopy reveals that plasma membrane "nanopore-like" structures (∼100-nm diameter) form rapidly due to lipid peroxidation, allowing calcium entry to initiate lysosome fusion. We posit that the extent of upstream damage to mammalian plasma membranes, calibrated by severity of nanopore-mediated local calcium influx for lysosome fusion, represents a biophysical mechanism for cell death induction.
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http://dx.doi.org/10.1083/jcb.201903176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147101PMC
April 2020

Forging New Strategies in the Cure of Human Oligometastatic Cancer.

JAMA Oncol 2020 05;6(5):659-660

Department of Radiation Oncology, Champalimaud Centre for the Unknown, Lisbon, Portugal.

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http://dx.doi.org/10.1001/jamaoncol.2020.0195DOI Listing
May 2020

Target motion mitigation promotes high-precision treatment planning and delivery of extreme hypofractionated prostate cancer radiotherapy: Results from a phase II study.

Radiother Oncol 2020 05 19;146:21-28. Epub 2020 Feb 19.

The Champalimaud Centre for the Unknown, Lisbon, Portugal; Memorial Sloan Kettering Cancer Center, New York, USA.

Background And Purpose: While favourable long-term outcomes have been reported in organ-confined prostate cancer treated with 5 × 7-8 Gy extreme hypofractionation, dose escalation to 5 × 9-10 Gy improved local control but was associated with unacceptable rates of late rectal and urinary toxicities. The purpose of this study was to explore the feasibility of intra-fractional prostate immobilization in reducing toxicity, to promote dose escalation with extreme hypofractionated radiotherapy in prostate cancer.

Material And Methods: 207 patients received 5 consecutive fractions of 9 Gy. An air-inflated (150 cm) endorectal balloon and an intraurethral Foley catheter with 3 beacon transponders were used to immobilize the prostate and monitor intra-fractional target motion. VMAT-IGRT with inverse dose-painting was employed in delivering the PTV dose and in sculpting exposure of normal organs at risk to fulfil dose-volume constraints.

Results: Introduction of air-filled balloon induced repeatable rectum/prostate complex migration from its resting position to a specific retropubic niche, affording the same 3D anatomical configuration daily. Intra-fractional target deviations ≤1 mm occurred in 95% of sessions, while target realignment in ≥2 mm deviations enabled treatment completion as scheduled. Nadir PSA at median 54 months follow-up was 0.19 ng/mL, and bRFS was 100%, 92.4% and 71.4% in low-, intermediate- and high-risk categories, respectively. Late Grade 2 GU and GI toxicities were 2.9% and 2.4%, respectively. No adverse changes in patient-reported quality of life scores were observed.

Conclusion: The unique spatial configuration of this prostate motion mitigation protocol enabled precise treatment planning and delivery that optimized outcomes of ultra-high 5 × 9 Gy hypofractionated radiotherapy of organ-confined prostate cancer.
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http://dx.doi.org/10.1016/j.radonc.2020.01.029DOI Listing
May 2020

Organoids Reveal That Inherent Radiosensitivity of Small and Large Intestinal Stem Cells Determines Organ Sensitivity.

Cancer Res 2020 03 5;80(5):1219-1227. Epub 2019 Nov 5.

Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York.

Tissue survival responses to ionizing radiation are nonlinear with dose, rather yielding tissue-specific descending curves that impede straightforward analysis of biologic effects. Apoptotic cell death often occurs at low doses, while at clinically relevant intermediate doses, double-strand break misrepair yields mitotic death that determines outcome. As researchers frequently use a single low dose for experimentation, such strategies may inaccurately depict inherent tissue responses. Cutting edge radiobiology has adopted full dose survival profiling and devised mathematical algorithms to fit curves to observed data to generate highly reproducible numerical data that accurately define clinically relevant inherent radiosensitivities. Here, we established a protocol for irradiating organoids that delivers radiation profiles simulating the organ of origin. This technique yielded highly similar dose-survival curves of small and large intestinal crypts and their cognate organoids analyzed by the single-hit multi-target (SHMT) algorithm, outcomes reflecting the inherent radiation profile of their respective Lgr5 stem cell populations. As this technological advance is quantitative, it will be useful for accurate evaluation of intestinal (patho)physiology and drug screening. SIGNIFICANCE: These findings establish standards for irradiating organoids that deliver radiation profiles that phenocopy the organ of origin..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056505PMC
March 2020

The evolving role of external beam radiotherapy in localized prostate cancer.

Semin Oncol 2019 06 22;46(3):246-253. Epub 2019 Aug 22.

The Champalimaud Centre for the Unknown, Lisbon, Portugal; Memorial Sloan Kettering Cancer Center, New York, New York.

Primary organ-confined prostate cancer is curable with external-beam radiotherapy. However, prostate cancer expresses a unique radiobiological phenotype, and its ablation requires doses at the high-end range of clinical radiotherapy. At this dose level, normal tissue radiosensitivity restricts the application of curative treatment, and mandates the use of the most advanced high-precision treatment delivery techniques to spare critical organs at risk. The efficacy and tolerance of dose-escalated conventional fractionated radiotherapy and of the biological equivalent doses of moderate and extreme hypofractionation are reviewed. Current studies indicate that novel risk-adapted techniques to spare normal organs at risk are still required to deploy high-biological equivalent dose extreme hypofractionation, while affording preservation of quality of life and cost-effectiveness.
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http://dx.doi.org/10.1053/j.seminoncol.2019.08.001DOI Listing
June 2019

Phenotype-Oriented Ablation of Oligometastatic Cancer with Single Dose Radiation Therapy.

Int J Radiat Oncol Biol Phys 2019 07 21;104(3):593-603. Epub 2019 Feb 21.

The Champalimaud Centre for the Unknown, Lisbon, Portugal; Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: The current oligometastatic (OM) model postulates that the disease evolves dynamically with sequential emergence of OM (SOM) lesions requiring successive rounds of SOM ablation to afford tumor cure. The present phase 2 study explores the ablative efficacy of 24 Gy single-dose radiation therapy (SDRT), its feasibility in diverse OM settings, and the impact of radioablation on polymetastatic (PM) dissemination.

Methods And Materials: One hundred seventy-five consecutive patients with 566 OM or SOM lesions underwent periodic positron emission tomography/computed tomography (PET/CT) imaging to stage the disease before treatment, determine tumor response, and monitor timing of PM conversion after SDRT. When 24 Gy SDRT was restricted by dose or volume constraints of serial normal organs, radioablation was diverted to a nontoxic 3×9 Gy SBRT schedule.

Results: SOM/SOMA occurred in 42% of the patients, and 24 Gy SDRT was feasible in 76% of the lesions. Despite 92% actuarial 5-year OM ablation by 24 Gy SDRT, respective PM-free survival (PMFS) was 26%, indicating PM conversion dominates over effective OM radioablation in many patients. Multivariate analysis of OM metrics derived from staging PET/CT scanning before first treatment predicted PMFS outcome after SDRT. Bivariate analysis of dichotomized high versus low baseline metric combinations of CT-derived tumor load (cutoff at 14.8 cm) and PET-derived metabolic SUV (cutoff at 6.5) yielded a 3-tiered PMFS categorization of 89%, 58% and 17% actuarial 5-year PMFS in categories 1, 2, and 3, respectively (P < .001), defining OM disease as a syndrome of diverse clinical and prognostic phenotypes.

Conclusion: Long-term risk of PM dissemination, predicted by preablation PET/CT staging, provides guidelines for phenotype-oriented OM therapy. In categories 1 and 2, radioablation should be a primary therapeutic element when pursuing tumor cure, whereas in the PM-prone category 3, radioablation should be a component of multimodal trials addressing primarily the risk of PM dissemination. PET/CT baseline staging also provides a platform for discovery of pharmacologically accessible PM drivers as targets for new phenotype-oriented treatment protocols.
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http://dx.doi.org/10.1016/j.ijrobp.2019.02.033DOI Listing
July 2019

Long-Term Implications of a Positive Posttreatment Biopsy in Patients Treated with External Beam Radiotherapy for Clinically Localized Prostate Cancer.

J Urol 2019 06;201(6):1127-1133

Departments of Radiation Oncology, Pathology and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center , New York , New York.

Purpose: We determined the prognostic importance of a positive posttreatment biopsy after prostate radiotherapy.

Materials And Methods: A total of 382 patients underwent a posttreatment biopsy after external beam radiotherapy for clinically localized prostate cancer. Posttreatment biopsies were classified as positive (prostatic adenocarcinoma without typical radiation induced changes), negative (no evidence of carcinoma) or adenocarcinoma with a severe treatment effect. Median followup in survivors was 9 years. Competing risks regression was used to assess relationships between prognostic predictors and cause specific mortality, distant metastasis and prostate specific antigen failure.

Results: The prevalence of positive biopsy, treatment effect and negative biopsy was 30%, 22% and 48%, respectively. Androgen deprivation therapy omission and high risk disease were associated with a 2.6 and 1.8-fold increase, respectively, in the odds of positive posttreatment biopsy. The 15-year PSA relapse rate associated with negative, severe treatment effect and positive posttreatment biopsies was 34%, 36% and 79%, respectively (p <0.001). After controlling for known predictors the risk of distant metastasis was 2.6-fold higher in patients with a positive biopsy (p <0.001) and cause specific mortality was twice as high in patients with a positive biopsy compared to those with negative and severe treatment effect biopsy outcomes (HR 2.00, p = 0.022).

Conclusions: A positive posttreatment biopsy after external beam radiotherapy was associated with a higher risk of distant metastasis and prostate cancer related death. Patients with severe treatment effect classified biopsies have biological characteristics more like patients with a negative biopsy than a positive biopsy. Posttreatment biopsies were more often positive in the setting of external beam radiotherapy alone without androgen deprivation therapy or in the presence of high risk disease.
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http://dx.doi.org/10.1097/JU.0000000000000110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543653PMC
June 2019

Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury.

J Clin Invest 2019 02 14;129(2):786-801. Epub 2019 Jan 14.

Laboratory of Signal Transduction.

Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3×9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention.
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http://dx.doi.org/10.1172/JCI97631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355243PMC
February 2019

Logarithmic expansion of LGR5 cells in human colorectal cancer.

Cell Signal 2018 Jan 25;42:97-105. Epub 2017 Sep 25.

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Stem cells of the small and large intestine are marked by expression of the Wnt target gene LGR5, a leucine-rich-repeat-containing G protein-coupled receptor. Previous studies reported increased expression of LGR5 in human colorectal cancer (CRC) compared to normal tissue either by immunohistochemistry or in situ hybridization (ISH). However, as these studies were semi-quantitative they did not provide a numerical estimate of the magnitude of this effect. While we confirm that LGR5 cells are exclusively located at the base of normal human small and large intestinal crypts, representing approximately 6% of total crypt cells, we show this cell population is 10-fold expanded in all grades of CRC, representing as much as 70% of the cells of tumor crypt-like structures. This expansion of the LGR5 compartment coincides with maintenance of crypt-like glandular structure (adenomas, and well and moderately differentiated adenocarcinomas), and is reduced in poorly differentiated CRC, where crypt-like glandular architecture is lost, accompanied by reduced epithelial terminal differentiation. Altogether these results indicate that LGR5 cell expansion is a hallmark of CRC tumorigenesis occurring during progression to adenoma, supporting CRC as a stem cell disease with implications for CRC therapy.
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http://dx.doi.org/10.1016/j.cellsig.2017.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766032PMC
January 2018

Gemcitabine kills proliferating endothelial cells exclusively via acid sphingomyelinase activation.

Cell Signal 2017 06 24;34:86-91. Epub 2017 Feb 24.

Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Gemcitabine is a widely-used anti-cancer drug with a well-defined mechanism of action in normal and transformed epithelial cells. However, its effect on endothelial cells is largely unknown. Acid sphingomyelinase (ASMase) is highly expressed in endothelial cells, converting plasma membrane sphingomyelin to pro-apoptotic ceramide upon activation by diverse stresses. In the current study, we investigated gemcitabine impact in primary cultures of endothelial cells. We find baseline ASMase increases markedly in bovine aortic endothelial cells (BAEC) as they transit from a proliferative to a confluent growth-arrested state. Further, gemcitabine activates ASMase and induces release of a secretory ASMase form into the media only in proliferating endothelial cells. Additionally, proliferative, but not growth-arrested BAEC, are sensitive to gemcitabine-induced apoptotic death, an effect blocked by inhibiting ASMase with imipramine or by binding ceramide on the cell surface with an anti-ceramide Ab. Confluent growth-arrested BAEC can be re-sensitized to gemcitabine-induced apoptosis by provision of exogenous sphingomyelinase. A highly similar phenotype was observed in primary cultures of human coronary artery endothelial cells. These findings reveal a previously-unrecognized mechanism of gemcitabine cytotoxicity in endothelium that may well contribute to its clinical benefit, and suggest the potential for further improvement of its clinical efficacy via pharmacologic modulation of ASMase/ceramide signaling in proliferative tumor endothelium.
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http://dx.doi.org/10.1016/j.cellsig.2017.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565230PMC
June 2017

Distinct Levels of Radioresistance in Lgr5 Colonic Epithelial Stem Cells versus Lgr5 Small Intestinal Stem Cells.

Cancer Res 2017 04 15;77(8):2124-2133. Epub 2017 Feb 15.

Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York.

Although small and large intestines possess seemingly similar Wnt-driven leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) adult epithelial stem cells, we report here that the two organs exhibit distinct mechanisms of tissue response to ionizing radiation. Employing transgenic mice and Lgr5 hybridization, we found colonic epithelial stem cells (CESC) markedly more radioresistant than small intestinal crypt base columnar stem cells (CBC; D = 6.0 ± 0.3 Gy vs. 1.3 ± 0.1, respectively; < 0.01). Accordingly, CESCs survived 30 Gy exposure, while CBCs were completely depleted after 15 Gy. EdU incorporation studies indicated that after 19 Gy, CBCs exited growth arrest at 12 hours, resuming normal mitotic activity despite 60% of this population displaying residual γH2AX foci, indicative of persistent unrepaired DNA damage. Checkpoint recovery before complete double-strand break (DSB) repair represents the of a newly defined potentially lethal pathophysiology termed checkpoint adaptation. In the small intestinal mucosa, checkpoint adaptation resulted in CBCs succumbing to an 8-fold increase in the incidence of highly lethal chromosomal aberrations and mitotic catastrophe by 48 hours postradiation. In contrast, Lgr5 CESCs displayed delayed checkpoint recovery at 48 hours post-19 Gy, coordinated with complete DSB repair and regeneration of colonic mucosa originating, at least in part, from surviving CESCs. The discovery that small intestinal CBCs succumb to checkpoint adaptation is the first demonstration that this aberrant cell-cycle response may drive mammalian tissue radiosensitivity. .
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http://dx.doi.org/10.1158/0008-5472.CAN-15-2870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621135PMC
April 2017

Targeting acid sphingomyelinase with anti-angiogenic chemotherapy.

Cell Signal 2017 01 1;29:52-61. Epub 2016 Oct 1.

Department of Radiation Oncology, USA. Electronic address:

Despite great promise, combining anti-angiogenic and conventional anti-cancer drugs has produced limited therapeutic benefit in clinical trials, presumably because mechanisms of anti-angiogenic tissue response remain only partially understood. Here we define a new paradigm, in which anti-angiogenic drugs can be used to chemosensitize tumors by targeting the endothelial acid sphingomyelinase (ASMase) signal transduction pathway. We demonstrate that paclitaxel and etoposide, but not cisplatin, confer ASMase-mediated endothelial injury within minutes. This rapid reaction is required for human HCT-116 colon cancer xenograft complete response and growth delay. Whereas VEGF inhibits ASMase, anti-VEGFR2 antibodies de-repress ASMase, enhancing endothelial apoptosis and drug-induced tumor response in asmase, but not in asmase, hosts. Such chemosensitization occurs only if the anti-angiogenic drug is delivered 1-2h before chemotherapy, but at no other time prior to or post chemotherapy. Our studies suggest that precisely-timed administration of anti-angiogenic drugs in combination with ASMase-targeting anti-cancer drugs is likely to optimize anti-tumor effects of systemic chemotherapy. This strategy warrants evaluation in future clinical trials.
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http://dx.doi.org/10.1016/j.cellsig.2016.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5138150PMC
January 2017

Spinal metastases: From conventional fractionated radiotherapy to single-dose SBRT.

Rep Pract Oncol Radiother 2015 Nov-Dec;20(6):454-63. Epub 2015 Apr 18.

Radiation Oncology, Champalimaud Centre for the Unknown, Lisbon, Portugal.

Aim: To review the recent evolution of spine SBRT with emphasis on single dose treatments.

Background: Radiation treatment of spine metastases represents a challenging problem in clinical oncology, because of the high risk of inflicting damage to the spinal cord. While conventional fractionated radiation therapy still constitutes the most commonly used modality for palliative treatment, notwithstanding its efficacy in terms of palliation of pain, local tumor control has been approximately 60%. This limited effectiveness is due to previous lack of technology to precisely target the tumor while avoiding the radiosensitive spinal cord, which constitutes a dose-limiting barrier to tumor cure.

Materials And Methods: A thorough review of the available literature on spine SBRT has been carried out and critically assessed.

Results: Stereotactic body radiotherapy (SBRT) emerges as an alternative, non-invasive high-precision approach, which allows escalation of tumor dose, while effectively sparing adjacent uninvolved organs at risk. Engaging technological advances, such as on-line Cone Beam Computed Tomography (CBCT), coupled with Dynamic Multi-Leaf Collimation (DMLC) and rapid intensity-modulated (IMRT) beam delivery, have promoted an interactive image-guided (IGRT) approach that precisely conforms treatment onto a defined target volume with a rapid dose fall-off to collateral non-target tissues, such as the spinal cord. Recent technological developments allow the use of the high-dose per fraction mode of hypofractionated SBRT for spinal oligometastatic cancer, even if only a few millimeters away from the tumor.

Conclusion: Single-dose spine SBRT, now increasingly implemented, yields unprecedented outcomes of local tumor ablation and safety, provided that advanced technology is employed.
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http://dx.doi.org/10.1016/j.rpor.2015.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661345PMC
December 2015

Targeting Homologous Recombination in Notch-Driven C. elegans Stem Cell and Human Tumors.

PLoS One 2015 29;10(6):e0127862. Epub 2015 Jun 29.

Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

Mammalian NOTCH1-4 receptors are all associated with human malignancy, although exact roles remain enigmatic. Here we employ glp-1(ar202), a temperature-sensitive gain-of-function C. elegans NOTCH mutant, to delineate NOTCH-driven tumor responses to radiotherapy. At ≤20°C, glp-1(ar202) is wild-type, whereas at 25°C it forms a germline stem cell⁄progenitor cell tumor reminiscent of human cancer. We identify a NOTCH tumor phenotype in which all tumor cells traffic rapidly to G2⁄M post-irradiation, attempt to repair DNA strand breaks exclusively via homology-driven repair, and when this fails die by mitotic death. Homology-driven repair inactivation is dramatically radiosensitizing. We show that these concepts translate directly to human cancer models.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127862PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485896PMC
March 2016
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