Peter Sidaway

Bio: Peter Sidaway is an academic researcher. The author has contributed to research in topics: Medicine & Cancer. The author has an hindex of 9, co-authored 194 publications receiving 429 citations.

CNS cancer: Glioblastoma subtypes revisited.

Abstract: classified into four subtypes (classical, neural, proneural, and mesenchymal) based on transcriptional features; however, the original classification, to varying degrees, included the transcriptomes of tumour-associated nonmalignant cells in the analysis. Now, the findings of a comprehensive longitudinal analysis of the GBM tumour transcriptome, excluding other cell types, reveal the existence of three (as opposed to four) distinct forms of GBM, and confirm the existence of GBM-subtype plasticity. First author Qianghu Wang explains, “our interest was motivated by the question of how tumours evolve over time, and whether they maintain their transcriptional subtype at different stages of tumour development. In order to address that question, we needed to make sure the classification was tumour-cell based and not microenvironment/nonmalignant-cell based”. Researchers distinguished GBM-specific mRNAs from those associated with nonmalignant cells using three methods: comparisons of patient samples with their matched cell cultures; sequencing of RNA from single GBM cells; and comparisons of core versus peripheral biopsy samples. The more-stringent separation of the transcriptomes of GBM and non-GBM cells revealed three subtypes that were strongly enriched with mRNAs associated with the classical, proneural, and mesenschymal subtypes; however, none of these subtypes showed any enrichment with mRNAs associated with the neural subtype, suggesting this subtype arose from contamination of the original samples with nontumour cells. Many GBM tumours have a high level of intratumour heterogeneity, as confirmed in this analysis. However, among patients with tumours with the lowest levels of heterogeneity, differences in median survival duration were observed between subgroups: 11.5, 14.7, and 17.0 months among those with mesenchymal, classical, or proneural tumours, respectively. Researchers then investigated the phenotypic plasticity of GBM using paired samples taken prior to treatment, and upon recurrence. A total of 91 pairs were analyzed using the renewed gene-signature methods revealing that only 55% of GBM samples retained their original subtype. Changes in the microenvironment were also monitored longitudinally: notable differences in the presence of several immune cell types were observed, including enrichment of hypermutated GBM with CD8+ T cells, suggesting sensitivity to CTLA-4 inhibition. In conclusion, the findings of this investigation shed new light on the clinical course and subtypes of GBM, which remains notoriously unresponsive to treatment. When asked about future directions, Co-corresponding author Roel Verhaak explains: “we are currently developing a reference dataset of 500 longitudinally profiled GBMs (as well as 500 samples of each of the other two major glioma types) as part of an international consortium”. He further adds that “longitudinally collected datasets, as reported in our study, are going to be front and centre in understanding how therapy resistance works in GBM”, whilst highlighting that “this work would not have been possible without substantial contributions from the other laboratories involved, led by Erik Sulman and Do-Hyun Nam”. Peter Sidaway C N S C A N C E R

MSI-H: a truly agnostic biomarker?

Abstract: 68 | FeBRuARY 2020 | volume 17 the median OS with surgery borders on being almost harmful ORIGINAL ARTICLE Coleman, R. L. et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N. Engl. J Med. 381, 1929–1939 (2019) For decades, patients with recurrent ovarian cancer have undergone secondary cytoreductive surgery (SCS). “The prevailing opinion, based on retrospective series and included in the National Comprehensive Cancer Network guidelines, was that surgery should be considered in selected patients,” summarizes lead investigator Robert Coleman. The results of the prospective randomized controlled GOG-0213 trial now indicate that SCS followed by chemotherapy does not improve overall survival (OS) over chemotherapy alone. “We designed GOG-0213 to answer two questions: does the addition of bevacizumab improve the effect of paclitaxel and carboplatin chemotherapy, and does secondary surgery improve survival outcomes,” explains Coleman. Women with platinumsensitive recurrent epithelial ovarian cancer were randomly assigned to SCS followed by platinumbased chemotherapy (n = 240) or chemotherapy alone (n = 245). At a median followup duration of 48.1 months, “the median OS with surgery borders on being almost harmful,” Coleman opines. Indeed, median OS durations were 50.6 months and 64.7 months with SCS and chemotherapy alone, respectively (HR 1.29, 95% CI 0.97–1.72; P = 0.08). Compared with incomplete resection, complete gross resection was associated with longer median OS durations: 56.0 months versus 37.8 months (HR 0.61, 95% CI 0.40–0.93). Complete gross resection did not, however, result in an OS benefit compared with chemotherapy alone: 56.0 months versus 64.7 months (HR 1.03, 95% CI 0.74–1.46). “We estimated OS durations of 22 months when we wrote the trial GY N A E C O LO G I C A L C A N C E R

Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials

Abstract: Summary Background Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood–brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. Methods An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0–2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG ( NCT02650401 ; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov , NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001). Findings Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77–18·76). 31 (57%; 95% CI 43·2–70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. Interpretation Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. Funding Ignyta/F Hoffmann-La Roche.

Acid-Activatable Versatile Micelleplexes for PD-L1 Blockade-Enhanced Cancer Photodynamic Immunotherapy

Abstract: Photodynamic therapy (PDT) has emerged as a promising clinical modality for cancer therapy due to its ability to initiate an antitumor immune response. However, PDT-mediated cancer immunotherapy is severely impaired by tumor-cell immunosuppression of host T cell antitumor activity through the programmed cell death 1 ligand (PD-L1) and programmed cell death receptor 1 (PD-1) (PD-L1–PD-1) immune checkpoint pathway. Here, we demonstrate that PDT-mediated cancer immunotherapy can be augmented by PD-L1 knockdown (KD) in tumor cells. We rationally designed a versatile micelleplex by integrating an acid-activatable cationic micelle, photosensitizer (PS), and small interfering RNA (siRNA). The micelleplex was inert at physiological pH conditions and activated only upon internalization in the acidic endocytic vesicles of tumor cells for fluorescence imaging and PDT. Compared to PDT alone, the combination of PDT and PD-L1 KD showed significantly enhanced efficacy for inhibiting tumor growth and distant metastasis i...

Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with high morbidity and mortality worldwide. To date, limited therapeutic achievements targeting cell proliferation and related mechanisms has led researchers to focus on the microenvironment where pancreatic cancers develop. The anomalous proliferation of stromal cells, such as pancreatic stellate cells, and an increased deposition of altered matrix proteins create an environment that facilitates tumor growth, metastasis and drug resistance. Here, we summarize our understanding of recent advances in research about the role of fibrosis in pancreatic cancer progression, with particular emphasize on the involvement of fibrotic machineries such as wound healing, extra cellular matrix degradation, and epithelial-to-mesenchymal transition. The precise influence of these mechanisms on the biological behaviors and growth of cancer cells has great impact on clinical therapy and therefore deserves more attention. We also discuss the role of various stromal components in conferring drug resistance to PDAC which further worsening the pessimistic disease prognosis. A more in depth understanding of cancer-stroma crosstalk within the tumor microenvironment and stroma based clinical and translational therapies may provide new therapeutic strategies for the prevention of pancreatic cancer progression.