Combination therapy for mCRPC with immune checkpoint inhibitors, ADT and vaccine: A mathematical model

Metastatic castration resistant prostate cancer (mCRPC) is commonly treated by androgen deprivation therapy (ADT) in combination with chemotherapy. Immune therapy by checkpoint inhibitors, has become a powerful new tool in the treatment of melanoma and lung cancer, and it is currently being used in clinical trials in other cancers, including mCRPC. However, so far, clinical trials with PD-1 and CTLA-4 inhibitors have been disappointing. In the present paper we develop a mathematical model to assess the efficacy of any combination of ADT with cancer vaccine, PD-1 inhibitor, and CTLA-4 inhibitor. The model is represented by a system of partial differential equations (PDEs) for cells, cytokines and drugs whose density/concentration evolves in time within the tumor. Efficacy of treatment is determined by the reduction in tumor volume at the endpoint of treatment. In mice experiments with ADT and various combinations of PD-1 and CTLA-4 inhibitors, tumor volume at day 30 was always larger than the initial tumor. Our model, however, shows that we can decrease tumor volume with large enough dose; for example, with 10 fold increase in the dose of anti-PD-1, initial tumor volume will decrease by 60%. Although the treatment with ADT in combination with PD-1 inhibitor or CTLA-4 inhibitor has been disappointing in clinical trials, our simulations suggest that, disregarding negative effects, combinations of ADT with checkpoint inhibitors can be effective in reducing tumor volume if larger doses are used. This points to the need for determining the optimal combination and amounts of dose for individual patients.

Gut mucus layer degradation is associated with aggressive cervical cancer phenotype

Background Gut microbiome community composition differs between cervical cancer (CC) patients and healthy controls, and increased gut diversity is associated with improved outcomes after treatment. We proposed that functions of specific microbial species adjoining the mucus layer may directly impact the biology of CC. Results In this study, we examined metagenomes of rectal swabs in 41 CC patients using whole-genome shotgun sequencing and found a significant association between molecular functions encoded by the metagenomes with markers of aggressive cancer including initial tumor size and stage. Profiling of the molecular function abundances and their distributions identified 2 microbial communities co-existing in each metagenome but with distinct metabolism and taxonomic structures. Community A (Clostridia and Proteobacteria predominant) was characterized by high activity of pathways involved in stress response, mucus glycan degradation and utilization of degradation byproducts. This community was prevalent in larger, advanced stage tumors. Conversely, community B (Bacteroidia predominant) was characterized by fast growth, active oxidative phosphorylation, and production of vitamins. This community was prevalent in small, early-stage tumors. Conclusions Based on these results, we propose that increased mucus layer degradation is associated with a more aggressive cervical cancer phenotype.

Dysregulation of Cytoskeleton Remodeling Drives Invasive Leading Cells Detachment

Detachment of cancer cells is the first step in tumor metastasis and malignancy. However, studies on the balance of initial tumor anchoring and detachment are limited. Herein, we revealed that the regulation of cytoskeleton proteins potentiates tumor detachment. The blockage of TGF-β1 using neutralizing antibodies induced cancer cell detachment in the Boyden chamber and 3D in-gel spheroid models. Moreover, treatment with latrunculin B, an actin polymerization inhibitor, enhanced cell dissociation by abolishing actin fibers, indicating that TGF-β1 mediates the formation of actin stress fibers, and is likely responsible for the dynamics of anchoring and detachment. Indeed, latrunculin B disrupted the formation of external TGF-β1-induced actin fibers and translocation of intracellular vinculin, a focal adhesion protein, resulting in the suppression of cell adhesion. Moreover, the silencing of vimentin substantially reduced cell adhesion and enhanced cell detachment, revealing that cell adhesion and focal adhesion protein translocation stimulated by TGF-β1 require vimentin. Using the 3D in-gel spheroid model, we found that latrunculin B suppressed the cell adhesion promoted by external TGF-β1, increasing the number of cells that penetrated the Matrigel and detached from the tumor spheres. Thus, cytoskeleton remodeling maintained the balance of cell anchoring and detachment, and the TGF-β1/vimentin/focal adhesion protein assembly axis was involved in the control dynamics of initial tumor detachment.

Metastasis and Tumor Cell Migration of Solid Tumors

The developmental process of local and distant metastases represents the major and defining trait of malignant tumors, whereby tumor cells sustain the capability to migrate from the initial tumor site, seed, and grow at a location other than that of the initial tumor [...]

INNV-05. MULTIDISCIPLINARY SPINE ONCOLOGY CARE ACROSS THE DISEASE CONTINUUM - UPDATES FOR THE BEDSIDE AND THE BOARDS

In response to the increased prevalence and complexity of metastatic and primary spine oncology, there has been a resultant increase in stakeholders, treatments and outcomes. A subset of the global multidisciplinary authors will present a timely and concise review of the contents of NOP’s Volume-7, supplement-1, “Multidisciplinary Spine Oncology Care Across the Disease Continuum”. The first portion will review: Epidemiology, Tumor Types, Presentation, Initial Tumor-directed Management, Initial Symptom-directed Management, Subsequent Tumor-directed Management, Subsequent Symptom-directed Management, and Multidisciplinary Program Development and Resources for Stakeholders. The second portion will challenge the current state of care and engage the attendees toward developing initiatives needed for a future state of care. Attendees will receive an update for both the bedside and the boards.

TAMI-46. FRIEND AND FOE: RADIATION THERAPY INCREASES GLIOBLASTOMA IMMUNE EVASION VIA EVS

Glioblastoma (GBM) is the most common primary malignant brain tumor and despite optimal treatment, long-term survival is extremely rare. Radiation therapy (RT) leads to successful initial tumor regression but recurrence is inevitable. Previous studies have shown that ionizing radiation leads to a change of immune-related markers on tumor cells. Extracellular vesicles (EVs) are membranous structures secreted by nearly every cell and have been shown drive GBM progression by acting as multifunctional signaling complexes. Here, we show that radiation of GBM cells leads to an altered EV secretion/uptake dynamic, composition, and protein content. Furthermore, we show that EVs secreted by radiated GBM cells modulate the innate (microglia/macrophages) as well as adaptive (T-cells) immune response in the tumor microenvironment. We dissected a novel mechanism by which GBM evades the immune system via EVs following RT, pointing towards novel therapeutic strategies to prevent GBM recurrence.

Migrations of cancer cells through the lens of phylogenetic biogeography

Malignant cells leave their initial tumor of growth and disperse to other tissues to form metastases. Dispersals also occur in nature when individuals in a population migrate from their area of origin to colonize other habitats. In cancer, phylogenetic biogeography is concerned with the source and trajectory of cell movements. We examine the suitability of primary features of organismal biogeography, including genetic diversification, dispersal, extinction, vicariance, and founder effects, to describe and reconstruct clone migration events among tumors. We used computer-simulated data to compare fits of seven biogeographic models and evaluate models’ performance in clone migration reconstruction. Models considering founder effects and dispersals were often better fit for the clone phylogenetic patterns, especially for polyclonal seeding and reseeding of metastases. However, simpler biogeographic models produced more accurate estimates of cell migration histories. Analyses of empirical datasets of basal-like breast cancer had model fits consistent with the patterns seen in the analysis of computer-simulated datasets. Our analyses reveal the powers and pitfalls of biogeographic models for modeling and inferring clone migration histories using tumor genome variation data. We conclude that the principles of molecular evolution and organismal biogeography are useful in these endeavors but that the available models and methods need to be applied judiciously.

Hearing loss and volumetric growth rate in untreated vestibular schwannoma

OBJECTIVE In this study, the authors aimed to clarify the relationship between hearing loss and tumor volumetric growth rates in patients with untreated vestibular schwannoma (VS). METHODS Records of 128 treatment-naive patients diagnosed with unilateral VS between 2012 and 2018 with serial audiometric assessment and MRI were reviewed. Tumor growth rates were determined from initial and final tumor volumes, with a median follow-up of 24.3 months (IQR 8.5–48.8 months). Hearing changes were based on pure tone averages, speech discrimination scores, and American Academy of Otolaryngology–Head and Neck Surgery hearing class. Primary outcomes were the loss of class A hearing and loss of serviceable hearing, estimated using the Kaplan-Meier method and with associations estimated from Cox proportional hazards models and reported as hazard ratios. RESULTS Larger initial tumor size was associated with an increased risk of losing class A (HR 1.5 for a 1-cm3 increase; p = 0.047) and serviceable (HR 1.3; p < 0.001) hearing. Additionally, increasing volumetric tumor growth rate was associated with elevated risk of loss of class A hearing (HR 1.2 for increase of 100% per year; p = 0.031) and serviceable hearing (HR 1.2; p = 0.014). Hazard ratios increased linearly with increasing growth rates, without any evident threshold growth rate that resulted in a large, sudden increased risk of hearing loss. CONCLUSIONS Larger initial tumor size and faster tumor growth rates were associated with an elevated risk of loss of class A and serviceable hearing.

Mathematical simulation and prediction of tumor volume using RBF artificial neural network at different circumstances in the tumor microenvironment

Uncontrolled proliferation of cells in a tissue caused by genetic mutations inside a cell is referred to as a tumor. A tumor which grows rapidly encounters a barrier when it grows to a certain size in presence of preexisting vasculature. This is the time when it has to find a way to go on the growth. The tumor starts to secrete tumor angiogenic factors (TAFs) and stimulate preexisting vessels to grow new sprouts. These new sprouts will find their way to the tumor in the extracellular matrix (ECM) by the gradient of TAF. As these new capillaries anastomose and reach tumor, fresh oxygen is available for the tumor and it will reinitiate the growth. Number of initial sprouts, distance of initial tumor cells from the vessel(s) and initial density of the tumor at the time of sprout formation are questions which are to be investigated. In the present study, the aim is to find the response of tumor cells and vessels to the reciprocal effects of each other in different circumstances in the tissue. Together with a mathematical formulation, a radial basis function (RBF) neural network is established to predict the number of tumor cells at different circumstances including size and distance of initial tumors from the parent vessel. A final formulation is given for the final number of tumor cells as a function of initial tumor size and distance between a parent vessel and a tumor. Results of this simulation demonstrate that, increasing the distance between a tumor and a parent vessel decreases the number of final tumor cells. Specially, this decrement becomes faster beyond a certain distance. Moreover, initial tumors in bigger domains must become much bigger before inducing angiogenesis which makes it harder for them to survive.

Gastrointestinal stromal tumor

Stromal tumors are the most common mesenchymal tumors in the digestive tract. Epidemiological data have shown an incidence of 11-20 per million people, the average age of diagnosis being 58 years. The location of these tumors can be anywhere on the gastrointestinal tract. The positive diagnosis is established by histopathological and immunohistochemical examination. The evolution of patients is correlated with the size of the initial tumor, the mitotic index and the topographic location. We present the case of a patient with an old anemic syndrome, considered deficiency anemia, with multiple hospitalizations, without response to substitution therapy that suddenly developed ascites. CT scan of the abdomen revealed a large abdominal tumor with jejunal origin. The positive diagnosis was established postoperatively by correlating the histopathological aspects with the immunohistochemical tests. The postoperative evolution was marked by complications, and one week later, the patient died secondary to a jejuno-colic fistula.