Project description:Although oncolytic viral vectors show promise for the treatment of various cancers, ineffective initial distribution and propagation throughout the tumor mass often limit the therapeutic response. A mathematical model is developed to describe the spread of herpes simplex virus from the initial injection site.The tumor is modeled as a sphere of radius R. The model incorporates reversible binding, interstitial diffusion, viral degradation, and internalization and physiologic parameters. Three species are considered as follows: free interstitial virus, virus bound to cell surfaces, and internalized virus.This analysis reveals that both rapid binding and internalization as well as hindered diffusion contain the virus to the initial injection volume, with negligible spread to the surrounding tissue. Unfortunately, increasing the dose to saturate receptors and promote diffusion throughout the tumor is not a viable option: the concentration necessary would likely compromise safety. However, targeted modifications to the virus that decrease the binding affinity have the potential to increase the number of infected cells by 1.5-fold or more. An increase in the effective diffusion coefficient can result in similar gains.This analysis suggests criteria by which the potential response of a tumor to oncolytic herpes simplex virus therapy can be assessed. Furthermore, it reveals the potential of modifications to the vector delivery method, physicochemical properties of the virus, and tumor extracellular matrix composition to enhance efficacy.
Project description:The distribution of nanomedicines inside solid tumors is often restricted to perivascular areas, leaving most distal tumor cells out of reach. This partly explains modest patient benefit of many nanomedicines compared to their free-form counterparts. The objective for this study is to develop a mathematical model to quantitatively analyze this phenomenon and the influencing factors to such perivascular distribution and seek for effective strategies to alleviate this. A spatial tumor distribution model was firstly constructed to mimic the geometrical structure of tumor vessels and the surrounding tumor cells. This tumor model was further integrated with a systemic pharmacokinetics model for nanoparticles. A variety of factors on the tumor spatial distributions of nanomedicines were considered in the model. With the model, we quantified the effect of these influencing factors on tumor delivery efficacy (ID %), the magnitude of heterogeneous distribution (H index), and the effect of enhanced permeability and retention (EPR). In particularly, we compared the spatial distributions of the nanoparticles and the free payloads insides tumors. The model predicted high degrees of distributional heterogeneity for both nanoparticles and free payloads. The degree of heterogeneity and the influencing factors for free payloads were markedly different from those for nanoparticles. We found that nanoparticle diffusion coefficient was the most effective factor in reducing the nanoparticle H index but exerted moderate influence on the free payloads H index. The most effective factor in reducing the H index of free payload was payload diffusion coefficient. The factors that improved free payload distribution were closely associated with higher drug efficacy. In contrast, the factors that improved nanoparticle spatial distributions did not always confer improved anti-tumor efficacy of the delivered drug. These findings highlight the importance of assessing the heterogeneous free payload distribution in tumors for the development of effective nanomedicines.
Project description:The emergence of immune 'checkpoint inhibitors' such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) has revolutionized treatment of solid tumors including melanoma, lung cancer, among many others. The goal of checkpoint inhibitor combination therapy is to improve clinical response and minimize toxicities. Rational design of checkpoint combinations considers immune-mediated mechanisms of antitumor activity: immunogenic cell death, antigen release and presentation, activation of T-cell responses, lymphocytic infiltration into tumors and depletion of immunosuppression. Potential synergistic combinations include checkpoint blockade with conventional (radiation, chemotherapy and targeted therapies) and newer immunotherapies (cancer vaccines, oncolytic viruses, among others). Reliable biomarkers are necessary to define patients who will achieve best clinical benefit with minimal toxicity in combination therapy.
Project description:Genomic instability is a hallmark of cancer related to DNA damage response (DDR) deficiencies, offering vulnerabilities for targeted treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) interfere with the efficient repair of DNA damage, particularly in tumors with existing defects in DNA repair, and induce synthetic lethality. PARPi are active across a range of tumor types harboring BRCA mutations and also BRCA-negative cancers, such as ovarian, breast or prostate cancers with homologous recombination deficiencies (HRD). Depending on immune contexture, immune checkpoint inhibitors (ICIs), such as anti-PD1/PD-L1 and anti-CTLA-4, elicit potent antitumor effects and have been approved in various cancers types. Although major breakthroughs have been performed with either PARPi or ICIs alone in multiple cancers, primary or acquired resistance often leads to tumor escape. PARPi-mediated unrepaired DNA damages modulate the tumor immune microenvironment by a range of molecular and cellular mechanisms, such as increasing genomic instability, immune pathway activation, and PD-L1 expression on cancer cells, which might promote responsiveness to ICIs. In this context, PARPi and ICIs represent a rational combination. In this review, we summarize the basic and translational biology supporting the combined strategy. We also detail preclinical results and early data of ongoing clinical trials indicating the synergistic effect of PARPi and ICIs. Moreover, we discuss the limitations and the future direction of the combination.
Project description:We aimed to identify key principles of targeted therapy of protein kinases and their application to the management of solid tumors.Concurrent advances in tumor genomic analysis and molecular inhibitor development have dramatically impacted the diagnosis and treatment of solid tumors, and common themes regarding the use of kinase inhibitors are developing.The list of kinase inhibitors that have been approved by the US Food and Drug Administration was reviewed and articles related to the agents were searched in the PubMed database up until December 2015. We included pivotal, randomized controlled phase 2 and 3 trials, and also pertinent preclinical studies.Small molecule inhibitors targeted against driver kinases, overactive in selected subsets of solid tumors, elicit improved response rates and survival compared with standard chemotherapy. Disease control has been proven in the metastatic and, to a limited extent, the adjuvant setting. However, tumor eradication is rare, and duration of treatment response is limited by the development of drug resistance.Kinase inhibitors induce response in diverse types of solid tumors. Although the agents are often effective in defined molecular subsets, cure is rare and resistance is common. This broad review provides rationale for further investigation of multimodality therapy combining kinase inhibitors with additional systemic and local therapies, including surgery.
Project description:The B-raf gene is mutated in up to 66% of human malignant melanomas, and its protein product, BRAF kinase, is a key part of RAS-RAF-MEK-ERK (MAPK) pathway of cancer cell proliferation. BRAF-targeted therapy induces significant responses in the majority of patients, and the combination BRAF/MEK inhibitor enhances clinical efficacy, but the response to BRAF inhibitor and to BRAF/MEK inhibitor is short lived. On the other hand, treatment of melanoma with an immune checkpoint inhibitor, such as anti-PD-1, has lower response rate but the response is much more durable, lasting for years. For this reason, it was suggested that combination of BRAF/MEK and PD-1 inhibitors will significantly improve overall survival time.This paper develops a mathematical model to address the question of the correlation between BRAF/MEK inhibitor and PD-1 inhibitor in melanoma therapy. The model includes dendritic and cancer cells, CD 4+ and CD 8+ T cells, MDSC cells, interleukins IL-12, IL-2, IL-6, IL-10 and TGF- β, PD-1 and PD-L1, and the two drugs: BRAF/MEK inhibitor (with concentration γ B ) and PD-1 inhibitor (with concentration γ A ). The model is represented by a system of partial differential equations, and is used to develop an efficacy map for the combined concentrations (γ B ,γ A ). It is shown that the two drugs are positively correlated if γ B and γ A are at low doses, that is, the growth of the tumor volume decreases if either γ B or γ A is increased. On the other hand, the two drugs are antagonistic at some high doses, that is, there are zones of (γ B ,γ A ) where an increase in one of the two drugs will increase the tumor volume growth, rather than decrease it.It will be important to identify, by animal experiments or by early clinical trials, the zones of (γ B ,γ A ) where antagonism occurs, in order to avoid these zones in more advanced clinical trials.
Project description:We present a mechanistic mathematical model of immune checkpoint inhibitor therapy to address the oncological need for early, broadly applicable readouts (biomarkers) of patient response to immunotherapy. The model is built upon the complex biological and physical interactions between the immune system and cancer, and is informed using only standard-of-care CT. We have retrospectively applied the model to 245 patients from multiple clinical trials treated with anti-CTLA-4 or anti-PD-1/PD-L1 antibodies. We found that model parameters distinctly identified patients with common (n = 18) and rare (n = 10) malignancy types who benefited and did not benefit from these monotherapies with accuracy as high as 88% at first restaging (median 53 days). Further, the parameters successfully differentiated pseudo-progression from true progression, providing previously unidentified insights into the unique biophysical characteristics of pseudo-progression. Our mathematical model offers a clinically relevant tool for personalized oncology and for engineering immunotherapy regimens.
Project description:Anti-programmed death (PD)-1 and PD-ligand (L)-1 checkpoint inhibitors have revolutionized the therapy of several cancers. Immunotherapy of cancer can offer long-term durable benefit to patients, is active regardless of tumour histology, has a unique immune-related safety profile, and can be used in combination with other cancer treatments. In addition, recent research has shown that immune-based therapy can be used as adjuvant therapy, that outcomes may be influenced by dose, and that clinical activity is observed in patients with brain metastases. Despite our increased understanding of these agents, there are still several important questions that need to be answered. These include strategies to overcome primary and acquired resistance, the influence of mutational status on treatment outcomes, the optimal duration of treatment, and the need to identify novel combination regimens that offer increased anti-tumour potency and/or reduced toxicity. Here we review recent developments in these areas, with particular focus on new data reported at the 2017 ASCO Annual Meeting.
Project description:Trypanosome RNA polymerase II transcription is polycistronic, individual mRNAs being excised by trans splicing and polyadenylation. In this study, we refined the previously published mathematical model for bloodstream form parasites and extended it to the procyclic form. We used the model, together with known mRNA half-lives, to predict the abundances of individual mRNAs, assuming rapid, unregulated mRNA processing; then we compared the results with measured mRNA abundances. Remarkably, the abundances of most mRNAs in procyclic forms are predicted quite well by the model, being largely explained by variations in mRNA decay rates and length. In bloodstream forms substantially more mRNAs are less abundant than predicted. We list mRNAs that are likely to show particularly slow or inefficient processing, either in both forms or with developmental regulation. We also measured ribosome occupancies of all mRNAs in trypanosomes grown in the same conditions as were used to measure mRNA turnover. In procyclic forms there was a weak positive correlation between ribosome density and mRNA half-life, suggesting cross-talk between translation and mRNA decay; ribosome density was related to the proportion of the mRNA on polysomes, indicating control of translation initiation. Ribosomal protein mRNAs in procyclics appeared to be exceptionally rapidly processed but poorly translated. Through this study, we conclude that lLevels of mRNAs in procyclic form trypanosomes are determined mainly by length and mRNA decay, with some control of precursor processing. In bloodstream forms variations in nuclear events play a larger role in transcriptome regulation, suggesting acquisition of new control mechanisms during adaptation to mammalian parasitism. Ribosome profiling and mRNA libraries were constructed in triplicate from in vitro PCF and in duplicate from in vitro T. brucei Lister427, to understand global differntial gene transcription.