Jeremy Karlin

Elective irradiation of pelvic lymph nodes during postprostatectomy salvage radiotherapy

Success rates with salvage radiotherapy (SRT) in men who have a postprostatectomy biochemical relapse are suboptimal. One treatment‐intensification strategy includes elective irradiation of the pelvic lymph nodes with whole pelvis radiotherapy (WPRT).

Identifying Appropriate Patients for Early Salvage Radiotherapy after Prostatectomy

PURPOSE It remains unclear whether relapsed prostate specific antigen at postprostatectomy salvage radiotherapy impacts outcomes as long it is 1.0 ng/ml or less. MATERIALS AND METHODS We performed a retrospective cohort study of 197 patients treated with salvage radiotherapy in the setting of detectable relapsed prostate specific antigen 1.0 ng/ml or less. Patients were excluded from analysis if they had lymph node involvement or received androgen deprivation therapy. Freedom from prostate specific antigen progression after salvage radiotherapy was analyzed by a Cox regression model. RESULTS Median relapsed prostate specific antigen was 0.33 ng/ml (range 0.07 to 1.0). There was 86% freedom from prostate specific antigen progression at a median followup of 52 months. Relapsed prostate specific antigen (HR 1.9, p = 0.004), Gleason score 8-10 (HR 5.2, p <0.001) and negative margin status (HR 2.0, p = 0.02) were independently associated with an increased risk of prostate specific antigen progression after salvage radiotherapy. We identified interaction between relapsed prostate specific antigen and Gleason score (p = 0.04) but not margin status. A significant association was noted between higher relapsed prostate specific antigen and prostate specific antigen progression after salvage radiotherapy in patients with Gleason score 8-10 but not 7 or less. In patients with Gleason score 8-10 the rate of freedom from prostate specific antigen progression at 53 months was 77% vs 26% when salvage radiotherapy was initiated at a relapsed prostate specific antigen of 0.33 or less vs 0.34 to 1.0 ng/ml (log rank p = 0.003). CONCLUSIONS Different relapsed prostate specific antigen thresholds for unsuccessful salvage radiotherapy may exist based on Gleason score. These data suggest that patients with Gleason score 8-10 should be offered salvage radiotherapy at the earliest detectable relapsed prostate specific antigen, even 0.33 ng/ml or less. Those with Gleason score 7 or less may have the opportunity to be followed with serial prostate specific antigen measurements to improve risk stratification, and delay and/or avoid the potential toxicity of salvage radiotherapy.

Management of Postprostatectomy Biochemical Relapse With Salvage Radiotherapy: Results of an International Survey.

Objectives:The management of patients with postprostatectomy salvage radiotherapy (SRT) presents radiation oncologists (ROs) with multiple treatment decisions that may impact outcomes. As the evidence addressing these issues is limited to retrospective data, it was hypothesized that widely disparate treatment paradigms exist. Methods:A 21-question survey was sent through SurveyMonkey to members of the American Society of Radiation Oncology. Results:A total of 999 ROs responded. Threshold rPSA values to initiate SRT ranged from 0.1 to 1 ng/mL. The highest dose prescribed by ROs ranged from <60 to >70.2 Gy. Elective lymph node irradiation was offered by 74%, and the majority (64%) referenced the Roach formula, Kattan nomogram, or D’Amico risk stratification to decide when it was appropriate. There was variability in pelvic field design with a preference to place the superior field border at either the upper, middle, or lower sacroiliac joint by 57.6%, 28.8%, and 13.6% of respondents, respectively. Adjuvant androgen deprivation therapy (ADT) was offered by 74%. Conclusions:Disparate treatment paradigms exist for SRT that may impact patient outcomes. Variability includes patient selection, treatment design, and recommendations for ADT. Many reference formulas to predict the benefit of pelvic lymph node irradiation that are not yet validated in the postprostatectomy setting. These data make it clear that well-designed, prospective clinical trials are needed to better evaluate the role of larger treatment fields, dose escalation, and ADT for the thousands of patients who are treated with postprostatectomy SRT each year.

Abstract 3041: Blood-brain barrier penetrating ATM inhibitor (AZ32) radiosensitises intracranial gliomas in mice

Ataxia-telangiectasia mutated (ATM) kinase is a central DNA damage response (DDR) component signalling the presence of DNA double strand breaks (DSBs) to DNA repair, checkpoint and survival pathways. Clinical doses of fractionated radiotherapy directed at tumours kill cells by inducing single strand breaks and DSBs, the latter being particularly lethal to all cells if not repaired. Poor survival rates of glioblastoma multiforme (GBM) patients is attributed to an inability to excise all invasive tumor tissue (if operable) and an intrinsic tumour chemo/radioresistance, which has been linked to elevated ATM activity in glioma stem cells. ATM inhibition (ATMi) radiosensitises cancer cell lines in vitro and in vivo. ATMi also acutely radiosensitises patient-derived glioma stem cells more effectively than by inhibiting other DDR or cell cycle checkpoint components (PARP, ATR, Chk1). Checkpoint-defective glioblastoma multiforme (GBM) cell lines seem to be particularly radio-sensitised by ATMi. In addition, several studies suggest that normal brain is radioprotected when ATM activity is deficient, suggesting ATM is required for apoptosis in neurons. ATMi in brain may therefore provide a wide therapeutic margin. Furthermore, ATM9s role in signalling DNA damage independent redox stress has been linked to promoting neoangiogenesis in tumour vasculature. Taken together, these studies suggest ATM is an extremely attractive target to inhibit during and potentially following radiotherapy. However, one impediment to preclinical and clinical studies is that current ATMi9s have limited CNS bioavailability. We report AZ32 as the first known selective, orally bioavailable blood-brain barrier (BBB) penetrating ATMi probe. AZ32 inhibits the DDR and radiosensitizes p53/checkpoint-defective GBM cells in vitro. Oral daily dosing providing sufficient mouse free brain pharmacokinetic exposures over AZ329s ATM IC50, during just four daily doses of whole brain irradiation results in significant improvement in median overall survival of syngeneic orthotopic mouse glioma models (log-rank AZ32/radiation vs. radiation p = 0.0194). Tumor eradication was confirmed by tumor imaging. This result was recapitulated with a human orthotopic model. These findings support the development of clinical grade BBB-penetrating ATMi as a potential treatment for GBM and potentially other intracranial tumours dosed in combination with fractionated radiotherapy used in standard clinical practice. Citation Format: Steve T. Durant, Jeremy Karlin, Kurt Pike, Nicola Colclough, N Mukhopadhyay, S F. Ahmad, J M. Bekta, M Tokarz, Catherine Bardelle, Gareth Hughes, Bhavika Patel, Andrew Thomason, Elaine Cadogan, Ian Barrett, Alan Lau, Martin Pass, Kristoffer Valerie. Blood-brain barrier penetrating ATM inhibitor (AZ32) radiosensitises intracranial gliomas in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3041.

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models

Preclinical data highlight AZD1390 as a potentially powerful new therapy to enhance brain tumor patient responses to radiotherapy. Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase–related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11C-labeled AZD1390 (Kp,uu, 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies.

Orally Bioavailable and Blood–Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice

Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited central nervous system (CNS) bioavailability; thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain. Both AZ31 and AZ32 blocked the DNA damage response and radiosensitized GBM cells in vitro. AZ32, with enhanced blood–brain barrier (BBB) penetration, was highly efficient in vivo as radiosensitizer in syngeneic and human, orthotopic mouse glioma model compared with AZ31. Furthermore, human glioma cell lines expressing mutant p53 or having checkpoint-defective mutations were particularly sensitive to ATMi radiosensitization. The mechanism for this p53 effect involves a propensity to undergo mitotic catastrophe relative to cells with wild-type p53. In vivo, apoptosis was >6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low-dose radiation. AZ32 is the first ATMi with oral bioavailability shown to radiosensitize glioma and improve survival in orthotopic mouse models. These findings support the development of a clinical-grade, BBB-penetrating ATMi for the treatment of GBM. Importantly, because many GBMs have defective p53 signaling, the use of an ATMi concurrent with standard radiotherapy is expected to be cancer-specific, increase the therapeutic ratio, and maintain full therapeutic effect at lower radiation doses. Mol Cancer Ther; 17(8); 1637–47. ©2018 AACR.

WE‐A‐BRB‐07: Critical Analysis of Strength‐Based Medical Event Definition in Prostate Seed Brachytherapy Based on a Comparative Retrospective Pre‐ and Post‐Implant Analysis

Purpose: To create a clinical basis and to describe a process that would lead to a better understanding of possible practical implementations of the treatment site concept in the strength‐base medical event definition. To explore various metrics and similarity measures defining the geometry of implants. Methods: Pre‐ and post‐implants were analyzed for 100 cases. Contour structures and seed data were extracted from Variseed (Varian Medical Systems, Inc., Palo Alto, CA). In house written Matlab software was developed to construct structures that would encompass 100% and 95% of seeds , identify seed distributions with greater than 20% of total number of seeds residing outside of ‘zones’ at distances up‐to 5 mm beyond the prostate contour, determine inter‐distances between seeds, and calculate the center of mass for prostate contours as well as seed distributions. Similarity between pre‐ and post‐implant plans was evaluated by skewness and kurtosis of the inter‐seed distance distributions. All implants studied were considered ‘good ’ or better by current D90 criteria. Results: In our dataset there were no cases in which more than 20% of the seeds were implanted outside a zone expanded 4mm from prostate. A 3mm expansion would have produced 5 events, while a 2mm expansion would have produced 11 events. Skewness of inter‐seed distances was on average 0.06 for pre‐plans and 0.14 for post‐plans. This demonstrates a displacement of inter‐seed distances toward larger values. Post to pre‐plan ratios of minimum box volume encompassing 95% of seeds increased from 1.3 to 1.72 as zones were expanded from 0 to 4mm. Kurtosis analysis revealed a significant increase in post‐plans, but outlier‐prone distributions did not correlate with the cases having more than 20% of seeds in distant zones. Conclusions: We are proposing measures based on clinical data that can assist in defining ‘treatment site’ as well as help practitioners better understand the relation between pre‐ and post‐implants.