Directed Evolution Restored Castrate Sensitivity in a Patient With Castrate Resistant Metastatic Prostate Cancer.

Objective: For centuries, humans have used directed evolution to promote desired traits in domesticated animals. We hypothesized similar strategies may be employed to steer castrate resistant prostate cancer cells to a castrate sensitive phenotype allowing resumption of Androgen Deprivation therapy (ADT) and prolonging survival.

Methods: Our interdisciplinary team investigated directed evolution to restore castrate sensitivity in a patient with metastatic castrate resistant prostate cancer who could not tolerate available therapeutic agents for castrate resistant disease.

The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease.

The development of de novo resistance is a major disadvantage in molecularly targeted therapies. While much focus is on cell-intrinsic mechanisms, the microenvironment is also known to play a crucial role. This study examines interactions between cancer cells and cancer associated fibroblasts (CAFs) to understand the local crosstalk facilitating residual disease.

PSA/testosterone ratio as a potential biomarker to identify early progressors of adaptive therapy in metastatic castration sensitive prostate cancer.

Purpose: We aim to identify biomarkers of progression in an ongoing pilot trial using adaptive dosing in metastatic castrate sensitive prostate cancer (mCSPC).

Patients And Methods: Men with mCSPC were given combined androgen deprivation therapy with an androgen receptor signaling inhibitor followed by a treatment break after achieving >75% PSA decline. This was followed by evolution-informed drug cycling to prevent resistance outgrowth.

Rapidly evolving orphan immunity genes protect human gut bacteria from intoxication by the type VI secretion system.

Bacteria encode diverse mechanisms for mediating interbacterial antagonism through the exchange of toxic effector proteins. Although the structure, function, and regulation of these pathways has been well established for many organisms, an understanding of their ecological and evolutionary dynamics lags behind. Type VI secretion systems (T6SS) deliver effectors between competing Gram-negative bacteria, including among mammalian gut Bacteroidales, resulting in the evolution of elaborate defense mechanisms that protect against T6SS attack.

Are Skin Lesion Superclinics Associated With Decision Fatigue? A Controlled, Observational Study.

Skin cancer superclinics have been proposed as an innovative solution to current capacity shortfalls. The aim of this study was to investigate whether this model was associated with decision fatigue. Consecutive patients with suspected skin cancer who attended a superclinic in 2022 were compared with those seen by the same clinician in standard clinics.

From structure to function: Decoding peptidoglycan O-acetylation in pathogenic bacteria.

Numerous pathogenic and non-pathogenic bacteria modulate the structure of their cell wall to escape the action of lytic enzymes that target it, threatening cell integrity. Of these modifications, the most taxonomically widespread is the addition of an acetyl to the C6 hydroxyl group of muramyl residues within the essential cell-wall heteropolymer peptidoglycan. This modification is found in many clinically important pathogens, including the WHO priority pathogens Neisseria gonorrhoeae, Staphylococcus aureus, Enterococcus faecium, and Streptococcus pneumoniae.

Multifactorial stroma-mediated resistance is a major contributor to residual disease under targeted therapies in lung cancers.

Despite inducing strong and durable clinical responses, targeted therapies do not eliminate advanced cancers, as a subset of tumor cells survives within residual tumors, eventually developing resistance. The ability of tumor cells to avoid therapeutic elimination can be mediated both by cell-intrinsic and microenvironmental mechanisms. Whilst the specific molecular mediators of cell-intrinsic and microenvironmental resistance are well understood, their relative contribution to therapeutic responses remains poorly defined.

The mechanism of peptidoglycan O-acetylation in Gram-negative bacteria typifies bacterial MBOAT-SGNH acyltransferases.

Bacterial cell envelope polymers are commonly modified with acyl groups that provide fitness advantages. Many polymer acylation pathways involve pairs of membrane-bound O-acyltransferase (MBOAT) and SGNH family proteins. As an example, the MBOAT protein PatA and the SGNH protein PatB are required in Gram-negative bacteria for peptidoglycan O-acetylation.

Deriving Optimal Treatment Timing for Adaptive Therapy: Matching the Model to the Tumor Dynamics.

Adaptive therapy (AT) protocols have been introduced to combat drug-resistance in cancer, and are characterized by breaks in maximum tolerated dose treatment (the current standard of care in most clinical settings). These breaks are scheduled to maintain tolerably high levels of tumor burden, employing competitive suppression of treatment-resistant sub-populations by treatment-sensitive sub-populations. AT has been integrated into several ongoing or planned clinical trials, including treatment of metastatic castrate-resistant prostate cancer, ovarian cancer, and BRAF-mutant melanoma, with initial clinical results suggesting that it can offer significant extensions in the time to progression over the standard of care.

Study protocol for Adaptive ChemoTherapy for Ovarian cancer (ACTOv): a multicentre phase II randomised controlled trial to evaluate the efficacy of adaptive therapy (AT) with carboplatin, based on changes in CA125, in patients with relapsed platinum-sensitive high-grade serous or high-grade endometrioid ovarian cancer.

Introduction: Adaptive ChemoTherapy for Ovarian cancer (ACTOv) is a phase II, multicentre, randomised controlled trial, evaluating an adaptive therapy (AT) regimen with carboplatin in women with relapsed, platinum-sensitive high-grade serous or high-grade endometrioid cancer of the ovary, fallopian tube and peritoneum whose disease has progressed at least 6 months after day 1 of the last cycle of platinum-based chemotherapy. AT is a novel, evolutionarily informed approach to cancer treatment, which aims to exploit intratumoral competition between drug-sensitive and drug-resistant tumour subpopulations by modulating drug dose according to a patient's own response to the last round of treatment. ACTOv is the first clinical trial of AT in this disease setting.

Oncolytic immunotherapy with nivolumab in muscle-invasive bladder cancer: a phase 1b trial.

There is a critical unmet need for safe and efficacious neoadjuvant treatment for cisplatin-ineligible patients with muscle-invasive bladder cancer. Here we launched a phase 1b study using the combination of intravesical cretostimogene grenadenorepvec (oncolytic serotype 5 adenovirus encoding granulocyte-macrophage colony-stimulating factor) with systemic nivolumab in cisplatin-ineligible patients with cT2-4aN0-1M0 muscle-invasive bladder cancer. The primary objective was to measure safety, and the secondary objective was to assess the anti-tumor efficacy as measured by pathologic complete response along with 1-year recurrence-free survival.

Spatial interactions modulate tumor growth and immune infiltration.

Direct observation of tumor-immune interactions is unlikely in tumors with currently available technology, but computational simulations based on clinical data can provide insight to test hypotheses. It is hypothesized that patterns of collagen evolve as a mechanism of immune escape, but the exact nature of immune-collagen interactions is poorly understood. Spatial data quantifying collagen fiber alignment in squamous cell carcinomas indicates that late-stage disease is associated with highly aligned fibers.

The mechanism of peptidoglycan O-acetylation in Gram-negative bacteria typifies bacterial MBOAT-SGNH acyltransferases.

Bacterial cell envelope polymers are commonly modified with acyl groups that provide fitness advantages. Many polymer acylation pathways involve pairs of membrane-bound -acyltransferase (MBOAT) and SGNH family proteins. As an example, the MBOAT protein PatA and the SGNH protein PatB are required in Gram-negative bacteria for peptidoglycan O-acetylation.

A novel combination therapy for ER+ breast cancer suppresses drug resistance via an evolutionary double-bind.

Chemotherapy remains a commonly used and important treatment option for metastatic breast cancer. A majority of ER+ metastatic breast cancer patients ultimately develop resistance to chemotherapy, resulting in disease progression. We hypothesized that an "evolutionary double-bind", where treatment with one drug improves the response to a different agent, would improve the effectiveness and durability of responses to chemotherapy.

Cell identity revealed by precise cell cycle state mapping links data modalities.

Several methods for cell cycle inference from sequencing data exist and are widely adopted. In contrast, methods for classification of cell cycle state from imaging data are scarce. We have for the first time integrated sequencing and imaging derived cell cycle pseudo-times for assigning 449 imaged cells to 693 sequenced cells at an average resolution of 3.

From yeast screening for suitability as single cell protein to fed-batch cultures.

Purpose: Fed-batch cultures have rarely been used in single cell protein (SCP) research. This work evaluated multiple yeast species for suitability as SCP cultivated using glucose- and sucrose-based substrate and performed in-depth studies of fed-batch SCP cultivation kinetics for selected yeasts, including determination of specific crude nitrogen-to-protein conversion factors.

Methods: SCP was cultivated using fully synthetic media in flask batch or bioreactor fed-batch cultures.

Spatial interactions modulate tumor growth and immune infiltration.

Lenia, a cellular automata framework used in artificial life, provides a natural setting to implement mathematical models of cancer incorporating features such as morphogenesis, homeostasis, motility, reproduction, growth, stimuli response, evolvability, and adaptation. Historically, agent-based models of cancer progression have been constructed with rules that govern birth, death and migration, with attempts to map local rules to emergent global growth dynamics. In contrast, Lenia provides a flexible framework for considering a spectrum of local (cell-scale) to global (tumor-scale) dynamics by defining an interaction kernel governing density-dependent growth dynamics.

Spatial analysis of recurrent glioblastoma reveals perivascular niche organization.

Tumor evolution is driven by genetic variation; however, it is the tumor microenvironment (TME) that provides the selective pressure contributing to evolution in cancer. Despite high histopathological heterogeneity within glioblastoma (GBM), the most aggressive brain tumor, the interactions between the genetically distinct GBM cells and the surrounding TME are not fully understood. To address this, we analyzed matched primary and recurrent GBM archival tumor tissues with imaging-based techniques aimed to simultaneously evaluate tumor tissues for the presence of hypoxic, angiogenic, and inflammatory niches, extracellular matrix (ECM) organization, TERT promoter mutational status, and several oncogenic amplifications on the same slide and location.

To modulate or to skip: De-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy.

Toxicity and emerging drug resistance pose important challenges in poly-adenosine ribose polymerase inhibitor (PARPi) maintenance therapy of ovarian cancer. We propose that adaptive therapy, which dynamically reduces treatment based on the tumor dynamics, might alleviate both issues. Utilizing in vitro time-lapse microscopy and stepwise model selection, we calibrate and validate a differential equation mathematical model, which we leverage to test different plausible adaptive treatment schedules.

Peristromal niches protect lung cancers from targeted therapies through a combined effect of multiple molecular mediators.

Targeted therapies directed against oncogenic signaling addictions, such as inhibitors of ALK in ALK+ NSCLC often induce strong and durable clinical responses. However, they are not curative in metastatic cancers, as some tumor cells persist through therapy, eventually developing resistance. Therapy sensitivity can reflect not only cell-intrinsic mechanisms but also inputs from stromal microenvironment.

Modeling tumors as species-rich ecological communities.

Many advanced cancers resist therapeutic intervention. This process is fundamentally related to intra-tumor heterogeneity: multiple cell populations, each with different mutational and phenotypic signatures, coexist within a tumor and its metastatic nodes. Like species in an ecosystem, many cancer cell populations are intertwined in a complex network of ecological interactions.