Prospects for complex mitochondrial therapy in oncology

Malignant tumors can be prevented, controlled, and cured. We could reduce the mortality of malignant tumor and improve prognosis of patients through screening and early detection and therapy. The prevention and control of malignant tumors in general population attach importance in China and series of blueprints and policies have been launched since last half a century. We have achieved remarkable progress in screening and early detection and therapy of malignant tumors with great support from government. We highlight the milestones of screening and early detection and therapy of malignant tumors in China and the organization and management of current national programs. We focus on the overview of eight malignant tumors included in current national screening programs. We summarize high quality evidence of screening of neoplasia in China. We reveal issues and challenges encountered in the practice currently and envisage where should we go in future for screening and early detection and therapy of tumors in China. We will further improve capacity of screening and early detection and therapy of tumor and promote action of prevention and control of tumor through implementation of policy of government leading, multiple cooperation, and involvement of whole society based on the guideline of prioritizing prevention, combining prevention and therapy, shifting forward of early detection, allocating the resource in low-income areas.

Solid tumor patients often suffer from cytopenias and are at risk for therapy-related myeloid neoplasms (tMN). Somatic mutations in leukemia-associated genes can occur in normal healthy individuals, referred to as clonal hematopoiesis (CH). CH is associated with cytopenias, risk of leukemia and cardiovascular disease. We and others have shown that CH is frequent in cancer patients. Characterization of the relationship between exposure to specific oncologic regimens and CH and how these relate to cytopenias and tMN risk would inform treatment decisions and tMN prevention strategies. To determine the relationship between CH and oncologic therapy we interrogated CH in a cohort of 9045 solid tumor patients. Subjects were sequenced using a targeted panel of cancer-associated mutations used to screen tumor samples against a blood control sample. Mutation detection was performed on blood-derived sequencing data using the matched tumor as a comparator and accounted for background sequencing error rates. CH was identified in 23% of patients. In multivariate regression analyses adjusted by age, CH was more often found in current smokers (OR=1.20, 95%CI=1.07-1.35, p<0.001) and less often found in Asians compared to Whites (OR=0.72, 95%CI=0.56-0.89, p<0.001). Smoking was associated with CH mutations in ASXL1 (OR=3.75, 95%CI=2.73-5.17, p<0.001). There was a higher proportion of patients with CH among those who had received chemotherapy (OR=1.14, 95%CI=1.02-1.26, p=0.02) and those who had received external beam radiation therapy (OR=1.45, 95%CI=1.28-1.63, p<0.001) prior to blood collection. Mutations in the DNA repair/cell cycle pathway (including TP53, PPM1D and CHEK2) were more common among patients who received chemotherapy and radiation therapy prior to IMPACT testing compared to those who were treatment naïve (p<0.001). Exposure to prior cytotoxic chemotherapy (OR=1.20, 95%CI=1.02-1.30; p=0.007) and radiation therapy (OR=1.6, 95%CI=1.4-1.9, p<0.001) was associated with having CH while exposure to immunotherapy and targeted therapy was not. Increasing cumulative dose of chemotherapy overall and cytotoxic therapy was associated with a higher likelihood of CH (p=0.015 and p=0.007 respectively). There was evidence of specific gene, treatment and dosage effects. To further examine the relationship between oncologic therapy and clonal evolution of CH, we collected 375 sequential samples at least 18 months apart. T mean change in VAF of CH mutations per year was found to increase by 0.17% in patients who did not receive further therapy during the follow-up time and 0.49% in those who were exposed to cytotoxic chemotherapy. A subset of patients with CH were consented to germline testing for cancer predisposition genes (N=6368). We observe a higher rate of CH among patients with a germline mutation in the cell cycle/DNA repair pathway (i.e. TP53) when compared to patients without germline mutations (OR=3.7, 95% CI: 1.35-9.35, p-value=0.01). CH is frequent in solid tumor patients and can be reliably detected when a matched tumor normal targeted gene sequencing approach is performed. Beyond age, CH is strongly associated with race, smoking and importantly prior exposure to oncologic therapy with evidence of specific treatment effects. Screening of CH in cancer cohorts is critical to the development of future clinical guidelines and risk-adapted prevention strategies for tMN. Note: This abstract was not presented at the meeting. Citation Format: Kelly Bolton, Ryan Ptashkin, Lior Braunstein, Teng Gao, Sean M. Devlin, Daniel Kelly, Catherine Coombs, Minal Patel, Matahi Moarii, Elsa Bernard, Antonin Berthon, Laura Boucai, Dominik Glodzik, Axel Martin, Zsofia Stadler, Michael Walsh, Diana Mandelker, Akshar Patel, Jessica Schulman, Gunes Gundem, Aijazuddin Syed, Maria Arcila, David B. Solit, Mark E. Robson, Marc Ladanyi, Choonsik Lee, John Philip, Dean Bajorin, Montserrat Garcia-Closas, Stuart Gardos, David Hyman, Martin Tallman, Mariko Yabe, Kenneth Offit, Howard Scher, Virginia Klimek, Luis Diaz, Nilanjan Chatterjee, Michael F. Berger, Lindsay Morton, Ross Levine, Ahmet Zehir, Elli Papaemmanuil. Oncologic therapy for solid tumors alters the risk of clonal hematopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-304.

Advance of the application of seaweed polysaccharides on antitumor drug delivery systems.

This study aims to improve the quality of clinical treatment and nursing care to standardize perioperative management for patients with liver tumors undergoing co-ablation system therapy. The Committee of Ablation Therapy in Oncology, China Anti-Cancer Association; the Expert Committee on Ablation Therapy; Chinese Society of Clinical Oncology (CSCO); and the Committee of Interventional, Perioperative, and Interventional Physician Branch of Chinese Medical Doctors Association organized medical and nursing experts in China. Based on the clinical practice of co-ablation system therapy in China and relevant domestic literature, an expert consensus about perioperative management was developed. The expert consensus included the key points of perioperative management, prevention, and care of complications; discharge guidance; and follow-up management for patients undergoing co-ablation system therapy of liver tumors. The consensus on the perioperative management of co-ablation system therapy for liver tumors has finally been formulated, serving as a reference and application for medical personnel in relevant fields based on hospital and patient conditions in clinical work.

In order to improve the quality of clinical therapy and nursing care for patients with lung tumors undergoing Co-Ablation System and standardize perioperative management, the Committee of Ablation Therapy in oncology, Chinese Anti-Cancer Association, and the Expert committee on Ablation Therapy and the Committee of Interventional Perioperative, Interventional Physician Branch of Chinese Medical Doctor Association organized medical and nursing experts in China. Based on the clinical practice of Co-Ablation System therapy in China and relevant domestic literature, a perioperative management expert consensus was developed. The expert consensus included the key points of perioperative nursing care, prevention and intervention of complications, and discharge guidance for Co-Ablation System therapy of lung tumors, to provide reference for the standardization and development of clinical management for lung tumors.

Systematic biobanking, novel imaging techniques, and advanced molecular analysis for precise tumor diagnosis and therapy: The Polish MOBIT project

Astragalus membranaceus (Astragalus), a traditional Chinese herbal medicine, is well known for its immunomodulatory effects. Recent studies have demonstrated that Astragalus exhibits antiviral, anti-inflammatory, anti-aging, anti-atherosclerotic, antioxidant, and immune-enhancing activities, as well as pro-apoptotic and cytotoxic effects on tumor cells. It is increasingly used as an adjuvant therapy in oncology. The mechanisms underlying its pro-apoptotic and cytotoxic activities include inhibition of tumor cell proliferation and migration, modulation of tumor-associated metabolic pathways, induction of tumor cell apoptosis, cell cycle arrest, regulation of autophagy, targeting of the tumor microenvironment, inhibition of neo-angiogenesis, and enhancement of host immunity. This review provides a comprehensive summary of the active metabolites of Astragalus and their pro-apoptotic and cytotoxic mechanisms, with a focus on metabolic regulation, offering a theoretical basis for its rational application in tumor therapy. Future research aimed at precise metabolite-guided interventions could improve patient outcomes and quality of life.

Comprehensive management of head and neck tumors : Thowley SE, Panje WR, Batsalsis JG, Lindberg RD (eds), with 140 contributors. Philadelphia, WB Saunders, 1987, 1917 pages, 2 volumes, 1127 illustrations, $180.00

Gene therapy was basically envisioned for the treatment of monogenic diseases, but soon the potential application area was extented – cancer gene therapy today covers two thirds of clinical studies. Gene transfer could strongly facilitate the sustained and locally confined delivery of proteins in specific tissues like tumors. The main approaches of gene therapy are ex vivo treatment of patient cells and in situ / in vivo administration of DNA. Vehicles for the transfer of DNA coding for therapeutic genes are either viruses incompetent of replication, like retroviral vectors or adenoviral vectors and lipid/peptide formulated DNA. Main approaches of gene therapy in oncology are ablation of tumor cells, immunotherapy/vaccination, tumor suppressor gene correction, and establishment of chemoresistance. Suicide gene transfer / prodrug treatment and infection of tumor cells with lytic viruses replicating exclusively in tumor tissue are the main issue of tumor cell ablation approaches. For immunotherapy, tumor cells are transduced/transfected ex vivo or in situ with genes like cytokines or costimulatory factors for the induction of cellular immune responses. Vaccination with cell lines expressing shared tumor-specific antigens or transplantation of allogeneic T cells to induce graft versus leukemia effects can be realized via the transfer of immunostimulatory or suicide genes. Other gene therapy approaches in oncology are the transfer of tumor suppressor genes into tumor cells carrying mutations of this gene or the induction of chemoresistance in bone marrow cells for high-dose chemotherapy treatment. Despite many anecdotal cases of success, the proof of a principle in cancer gene therapy was not yet demonstrated in statistically relevant clinical trials. However, gene therapy is offering many ways to enhance tumor treatment. The coming years of preclinical and clinical development should result in a deeper understanding of how gene therapy can improve cancer treatment.

Pain caused by the tumor or aromatase inhibitors (AIs) is a disabling symptom in breast cancer survivors. Their mechanisms are unclear, but pro-algesic and inflammatory mediators seem to be involved. Kinins are endogenous algogenic mediators associated with various painful conditions via B1 and B2 receptor activation, including chemotherapy-induced pain and breast cancer proliferation. We investigate the involvement of the kinin B1 and B2 receptors in metastatic breast tumor (4T1 breast cancer cells)-caused pain and in aromatase inhibitors (anastrozole or letrozole) therapy-associated pain. A protocol associating the tumor and antineoplastic therapy was also performed. Kinin receptors’ role was investigated via pharmacological antagonism, receptors protein expression, and kinin levels. Mechanical and cold allodynia and muscle strength were evaluated. AIs and breast tumor increased kinin receptors expression, and tumor also increased kinin levels. AIs caused mechanical allodynia and reduced the muscle strength of mice. Kinin B1 (DALBk) and B2 (Icatibant) receptor antagonists attenuated these effects and reduced breast tumor-induced mechanical and cold allodynia. AIs or paclitaxel enhanced breast tumor-induced mechanical hypersensitivity, while DALBk and Icatibant prevented this increase. Antagonists did not interfere with paclitaxel's cytotoxic action in vitro. Thus, kinin B1 or B2 receptors can be a potential target for treating the pain caused by metastatic breast tumor and their antineoplastic therapy.

The advent of microarrays over the past decade has transformed the way genome-wide studies are designed and conducted, leading to an unprecedented speed of acquisition and amount of new knowledge. Microarray data have led to the identification of molecular subclasses of solid tumors characterized by distinct oncogenic pathways, as well as the development of multigene prognostic or predictive models equivalent or superior to those of established clinical parameters. In the field of molecular-targeted therapy for cancer, in particular, the application of array-based methodologies has enabled the identification of molecular targets with 'key' roles in neoplastic transformation or tumor progression and the subsequent development of targeted agents, which are most likely to be active in the specific molecular setting. Herein, we present a summary of the main applications of whole-genome expression microarrays in the field of molecular-targeted therapies for solid tumors and we discuss their potential in the clinical setting. An emphasis is given on deciphering the molecular mechanisms of drug action, identifying novel therapeutic targets and suitable agents to target them with, and discovering molecular markers/signatures that predict response to therapy or optimal drug dose for each patient.

The advent of imatinib mesilate, an oral target therapy, has dramatically changed the natural history of gastrointestinal stromal tumours (GISTs). This rare neoplasm has become the paradigm of targeted therapies in solid tumours, also introducing a home-based cure concept in oncology. However, it should be retained that oral drug administration entails new and relevant management problems. Multiple studies have demonstrated the efficacy of imatinib in GISTs associated with a good toxicity profile. However, the efficacy of imatinib, according to its mechanism of action and pharmacokinetics, is closely related to daily assumption. No interruption or "jerky" assumption is permitted in order to avoid efficacy loss. Thus, the issue of treatment adherence is crucial for a successful strategy and should not be overlooked. We think that dealing with the problem means assessing a wide spectrum of not only clinical and general but also psychological and individual aspects. Furthermore, both patient and family should play an active role in the "cure process" and physicians should reduce the distance separating them from their patients due to home-based target therapy, promoting communication and consolidation of a trust-based physician-patient relationship. Several advantages have been introduced by oral target therapies in oncology. However, chronic drug administration, even if generally well tolerated, when prolonged for an undetermined time could heavily impact on patients' quality of life. This could induce non-prescribed drug suspension, with negative impact on disease control. More studies would be necessary in order to detect real patients' adherence, to correlate drug assumption with clinical outcome and to optimize imatinib treatment strategy.

Adoptive cell therapies (ACTs) have shown transformative efficacy in oncology with five US Food and Drug Administration (FDA) approvals for chimeric antigen receptor (CAR) T‐cell therapies in hematological malignancies, and promising activity for T cell receptor T‐cell therapies in both liquid and solid tumors. Clinical pharmacology can play a pivotal role in optimizing ACTs, aided by modeling and simulation toolboxes and deep understanding of the underlying biological and immunological processes. Close collaboration and multilevel data integration across functions, including chemistry, manufacturing, and control, biomarkers, bioanalytical, and clinical science and safety teams will be critical to ACT development. As ACT is comprised of alive, polyfunctional, and heterogeneous immune cells, its overall physicochemical and pharmacological property is vastly different from other platforms/modalities, such as small molecule and protein therapeutics. In this review, we first describe the unique kinetics of T cells and the appropriate bioanalytical strategies to characterize cellular kinetics. We then assess the distinct aspects of clinical pharmacology for ACTs in comparison to traditional small molecule and protein therapeutics. Additionally, we provide a review for the five FDA‐approved CAR T‐cell therapies and summarize their properties, cellular kinetic characteristics, dose‐exposure‐response relationship, and potential baseline factors/variables in product, patient, and regimen that may affect the safety and efficacy. Finally, we probe into existing empirical and mechanistic quantitative techniques to understand how various modeling and simulation approaches can support clinical pharmacology strategy and propose key considerations to be incorporated and explored in future models.

Gastrointestinal stromal tumors (GISTs) comprise a recently defined entity of the most common mesenchymal neoplasms of the gastrointestinal tract. Advances in the understanding of the molecular mechanisms of GIST pathogenesis have resulted in the development of a treatment approach which has become a model of targeted therapy in oncology. The introduction of imatinib mesylate (inhibiting KIT/PDGFRA (platelet-derived growth factor receptor-alpha) and their downstream signaling cascade) has revolutionized the therapy of advanced (inoperable and/or metastatic) GISTs. Imatinib has now become the standard of care in the treatment of patients with advanced GIST. However, a majority of patients eventually develop clinical resistance to imatinib. Over the last few years major progress has been made in elucidating the mechanism of disease progression (as secondary mutations in KIT and/or PDGFRA kinase domains) and resistance to imatinib. Currently, the sole approved second-line drug is sunitinib--a multitargeted agent, an inhibitor of tyrosine kinase, of KIT and PDGFRA/B and of the vascular endothelial growth factor receptors (VEGFRs)-1, -2 and 3, FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell-line derived neurotrophic factor receptor (REarranged during Transfection; RET). However, a number of new generation tyrosine kinase inhibitors, alone or in combination, are being evaluated at present alongside treatment options alternative to inhibiting the KIT signaling pathway (as heat shock protein 90 or mammalian target of rapamycin). This article discusses the factors relating to imatinib resistance as well as upcoming potentially effective treatment options for patients with progressive disease available in 2008 and those under investigation with more individualized treatment methods, which has been recently patented. This review focuses on the current achievements in targeted therapy of advanced GISTs, and how the insight into the resistance mechanisms may allow in the near future to treat patients with advanced GISTs.

Advances in the understanding of the molecular mechanisms of gastrointestinal stromal tumors (GISTs) pathogenesis have resulted in the development of a treatment approach which has become a model of targeted therapy in oncology. The introduction of imatinib mesylate [inhibiting KIT/PDGFRA (platelet-derived growth factor receptor-α) and their downstream signaling cascade] has dramatically improved the therapy of advanced (inoperable and/or metastatic) GIST. Imatinib has now become the standard of care in the treatment of patients with advanced GIST and its efficacy has been proven also in adjuvant setting after resection of primary high-risk tumors. However, a majority of patients eventually develop resistance to imatinib. Over the last few years, significant progress has been made in elucidating the mechanism of disease progression (as secondary mutations in KIT and/or PDGFRA kinase domains) and resistance to imatinib. Currently, the second-line approved drug is sunitinib—a multikinase inhibitor of KIT and PDGFRA/B and of the vascular endothelial growth factor receptors (VEGFRs)-1, -2, and 3, FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell-line derived neurotrophic factor receptor [Rearranged during Transfection (RET)], and in the third line, regorafenib was approved recently. However, a number of new generation tyrosine kinase inhibitors (as ponatinib) are being evaluated at present alongside treatment options alternative to inhibiting the KIT signaling pathway (as heat shock protein 90 or insulin-like growth factor 1 receptor).KeywordsGastrointestinal stromal tumorKITPDGFRImatinibSunitinibRegorafenib