Adaptive therapy achieves long-term control of chemotherapy resistance in high grade ovarian cancer.

Drug resistance results in poor outcomes for most patients with metastatic cancer. Adaptive Therapy (AT) proposes to address this by exploiting presumed fitness costs incurred by drug-resistant cells when drug is absent, and prescribing dose reductions to allow fitter, sensitive cells to re-grow and re-sensitise the tumour. However, empirical evidence for treatment-induced fitness change is lacking. We show that fitness costs in chemotherapy-resistant ovarian cancer cause selective decline and apoptosis of resistant populations in low-resource conditions. Moreover, carboplatin AT caused fluctuations in sensitive/resistant tumour population size in vitro and significantly extended survival of tumour-bearing mice. In sequential blood-derived cell-free DNA and tumour samples obtained longitudinally from ovarian cancer patients during treatment, we inferred resistant cancer cell population size through therapy and observed it correlated strongly with disease burden. These data have enabled us to launch a multicentre, phase 2 randomised controlled trial (ACTOv) to evaluate AT in ovarian cancer.

The role of PARP inhibitor combination therapy in ovarian cancer.

The use of PARP inhibitors (PARPi) has transformed the care of advanced high-grade serous/endometrioid ovarian cancer. PARPi are now available to patients in both the first-line and recurrent platinum-sensitive disease settings; therefore, most patients will receive PARPi at some point in their treatment pathway. The majority of this expanding population of patients eventually acquire resistance to PARPi, in addition to those with primary PARPi resistance. We discuss the rationale behind developing combination therapies, to work synergistically with PARPi and overcome mechanisms of resistance to restore drug sensitivity, and clinical evidence of their efficacy to date.

Learning from Crisis: a Multicentre Study of Oncology Telemedicine Clinics Introduced During COVID-19.

The COVID-19 pandemic has necessitated adaptation of cancer patient care. Oncology patients who contract COVID-19 have poor outcomes. Telemedicine clinics (teleclinics) have been introduced for cancer patients to reduce the risk of horizontal transmission at St. Bartholomew's Hospital and The Royal Free Hospital in London. Teleclinics have become routine in many specialities; however, inclusion in oncology care was not standard prior to the pandemic. A mixed-methods survey was designed and delivered to cancer patients (n = 106) at St. Bartholomew's Hospital and The Royal Free Hospital who had transitioned to teleclinics in March 2020. The survey explored patients' perceptions of this format. In total, 96 (90.5%) patients consented to take part, across a range of tumour types. Overall, respondents reacted favourably to the format of the teleclinics, with 90.6% of respondents (87/96) stating they would utilise teleclinics beyond the pandemic. Additionally, a survey was distributed to clinicians delivering these teleclinics (n = 16) to explore previous training in, perceptions of, and lessons learned from the introduction of telemedicine. Results suggest patients are accepting of teleclinic use for most clinical purposes. Teleclinic implementation affords benefits to cancer patient care both during and after COVID-19, but there is an urgent need for telemedicine education in oncology specialty training.

LiquidCNA: Tracking subclonal evolution from longitudinal liquid biopsies using somatic copy number alterations.

Cell-free DNA (cfDNA) measured via liquid biopsies provides a way for minimally invasive monitoring of tumor evolutionary dynamics during therapy. Here we present liquidCNA, a method to track subclonal evolution from longitudinally collected cfDNA samples sequenced through cost-effective low-pass whole-genome sequencing. LiquidCNA utilizes somatic copy number alteration (SCNA) to simultaneously genotype and quantify the size of the dominant subclone without requiring B-allele frequency information, matched-normal samples, or prior knowledge on the genetic identity of the emerging clone. We demonstrate the accuracy of liquidCNA in synthetically generated sample sets and in vitro mixtures of cancer cell lines. In vivo application in patients with metastatic lung cancer reveals the progressive emergence of a novel tumor subpopulation. LiquidCNA is straightforward to use, is computationally inexpensive, and enables continuous monitoring of subclonal evolution to understand and control-therapy-induced resistance.

The role of MET in chemotherapy resistance.

Chemotherapy remains the mainstay of treatment in the majority of solid and haematological malignancies. Resistance to cytotoxic chemotherapy is a major clinical problem and substantial research is ongoing into potential methods of overcoming this resistance. One major target, the receptor tyrosine kinase MET, has generated increasing interest with multiple clinical trials in progress. Overexpression of MET is frequently observed in a range of different cancers and is associated with poor prognosis. Studies have shown that MET promotes resistance to targeted therapies, including those targeting EGFR, BRAF and MEK. More recently, several reports suggest that MET also contributes to cytotoxic chemotherapy resistance. Here we review the preclinical evidence of MET's role in chemotherapy resistance, the mechanisms by which this resistance is mediated and the translational relevance of MET inhibitor therapy for patients with chemotherapy resistant disease.

Is oestrogen neuroprotective?

Neuro-protection in this context is an important concept in the treatment of patients in the early, prodromal phase of psychosis, otherwise known as the 'At Ultra High Risk Mental State'. Neuro-protection as described here refers to the use of agents to control the process of apoptosis, which occurs more rapidly in the earliest phases of schizophrenia. There is a need to identify medications with fewer side effects than anti-psychotics in order to treat at risk mental states, or prodromal psychosis. Studies have shown that schizophrenia occurs in males at an earlier age than females. Later, at about the time of the menopause, there is a second peak in the incidence of psychosis (schizophrenia) in women. Hence it has been suggested that Oestrogen may be neuroprotective. Studies have shown that the addition of oestradiol to anti-psychotics in the treatment of schizophrenia in females increased the efficacy of the treatment, which suggests that oestrogen does indeed have a neuroprotective action. However oestrogen has never been used in 'at ultra high risk mental states', perhaps because of concern regarding side effects.