Objective Development of computational approaches and tools to effectively integrate multidomain data is urgently needed for the development of newly targeted cancer therapeutics.
Methods We proposed ...an integrative network-based infrastructure to identify new druggable targets and anticancer indications for existing drugs through targeting significantly mutated genes (SMGs) discovered in the human cancer genomes. The underlying assumption is that a drug would have a high potential for anticancer indication if its up-/down-regulated genes from the Connectivity Map tended to be SMGs or their neighbors in the human protein interaction network.
Results We assembled and curated 693 SMGs in 29 cancer types and found 121 proteins currently targeted by known anticancer or noncancer (repurposed) drugs. We found that the approved or experimental cancer drugs could potentially target these SMGs in 33.3% of the mutated cancer samples, and this number increased to 68.0% by drug repositioning through surveying exome-sequencing data in approximately 5000 normal-tumor pairs from The Cancer Genome Atlas. Furthermore, we identified 284 potential new indications connecting 28 cancer types and 48 existing drugs (adjusted P < .05), with a 66.7% success rate validated by literature data. Several existing drugs (e.g., niclosamide, valproic acid, captopril, and resveratrol) were predicted to have potential indications for multiple cancer types. Finally, we used integrative analysis to showcase a potential mechanism-of-action for resveratrol in breast and lung cancer treatment whereby it targets several SMGs (ARNTL, ASPM, CTTN, EIF4G1, FOXP1, and STIP1).
Conclusions In summary, we demonstrated that our integrative network-based infrastructure is a promising strategy to identify potential druggable targets and uncover new indications for existing drugs to speed up molecularly targeted cancer therapeutics.
Purpose
Several targeted agents demonstrated efficacy in early clinical trials for gastrointestinal (GI) cancers, but in many cases, phase-III trials and/or approval by the European Medicines Agency ...(EMA) are lacking. The primary focus of this study was to assess the regulatory processes associated with use and reimbursement of off-label treatment in precision oncology and to evaluate the benefit of targeted therapy in a real-world population in Germany.
Methods
Our cohort comprises 137 patients with GI cancers and is biased towards cancer entities with a high frequency of known targetable alterations, such as cholangiocarcinoma. Genetic testing was used to identify molecular targets, and therapy response was evaluated based on CT scans.
Results
A molecular target for precision oncology was identified in 53 patients and 43 requests for cost coverage were submitted to health insurance companies. 60% of the requests received approval after initial application and another 7% after appeal. Half of the rejected requests were denied despite ESCAT IA level evidence. The median time between initiation of molecular testing and start of therapy was 75 days. 35 patients received matched targeted therapies (
n
= 28) or, in the case of MSI, immunotherapy (IO) (
n
= 7). We observed a trend in favor of molecular therapy when compared to the immediate prior treatment.
Conclusion
Relevant treatment options were identified by molecular testing in a significant subset of patients. When targeted therapies that lack EMA approval are considered, treatment initiation may be delayed by the duration of the molecular analysis and the regulatory processes.
Introduction: Prostate cancer is one of the most common malignancies affecting men worldwide, which poses a serious health risk due to its high incidence and impact on quality of life. Despite ...advances in the diagnosis and treatment of this condition, the management of advanced and aggressive forms of the disease remains complex. Aim of the Study: The aim of this study is to review current diagnostic methods, treatment strategies and prognostic factors in prostate cancer, that a particular focus on personalized medicine and multidisciplinary approaches to improve patient outcomes. Materials and Methods: A comprehensive literature review was conducted using PubMed sources and other scientific databases, focusing on currently available publications. The literature available in the PubMed database was reviewed using the following keywords: “prostate cancer” “prostate cancer diagnosis”, “prostate cancer treatment”, “personalized medicine for prostate cancer”, “physical activity in prostate cancer”. The review included studies on prostate cancer epidemiology, pathogenesis, advances in diagnosis, treatment, physical activity and future research directions. Conclusions: Advances in diagnostic technologies and emerging new therapies have significantly improved the prognosis for patients with prostate cancer. However, continued research and commitment to personalized treatment strategies are essential to meet the challenges of advanced disease. Multidisciplinary collaboration and patient-centered care remain key to optimizing outcomes and improving quality of life for prostate cancer patients.
During tumor progression, the size and location of the tumor are important factors closely associated with the metastatic potential of the cancer as they largely govern tumor hypoxia and ...angiogenesis. However, despite the achievements of previous studies, these critical factors are poorly studied, mainly due to the lack of a flexible technique that can readily control 3D tumor mimicking constructs and their spatial relations with vasculature. Here, a novel tissue‐level platform consisting of a metastatic cancer unit (MCU) and a perfusable vascular endothelium system (VES) is presented using in situ 3D cell printing. Size‐tunable and position‐controllable 3D cancer spheroids (500–1000 µm) are directly printed within the established bath bioink with a self‐driven perfusable vascular channel. The cancer‐vascular interactions are generated through controlling the distance between MCU and VES to investigate metastasis‐associated changes at adjacent and distal regions. The result shows that MCU in 600 µm diameter includes hypoxia, invasion, and angiogenetic signaling. The further observations demonstrate that the proximity of MCU to VES augments the epithelial‐mesenchymal transition (EMT) in MCU and vascular dysfunction/inflammation in VES, corroborating the positional significance in tumor metastasis. The platform with the precise‐positioning control enables the recapitulation of patient's detailed metastatic progression, opening the chance for precision cancer medicine.
Here, a novel tissue‐level platform consisting of metastatic cancer units (MCUs) and a perfusable vascular endothelium system (VES) is presented using in situ 3D cell printing. Size‐tunable and position‐controllable 3D cancer spheroids are directly printed within the supporting bath with a perfusable vascular channel. The cancer‐vascular interactions are generated through controlling the distance between MCU and VES.
Future options for the management of stage IV colorectal cancer are primarily focused on personalized and directed therapies. Interventions include precision cancer medicine, utilizing nanocarrier ...platforms for directed chemotherapy, palliative pressurized intraperitoneal aerosol chemotherapy (PIPAC), adjunctive oncolytic virotherapy, and radioembolization techniques. Comprehensive genetic profiling provides specific tumor-directed therapy based on individual genetics. Biomimetic magnetic nanoparticles as chemotherapy delivery systems may reduce systemic side effects of traditional chemotherapy by targeting tumor cells and sparing healthy cells. PIPAC is a newly emerging option for patients with peritoneal metastasis from colorectal cancer and is now being used internationally, showing promising results as a palliative therapy for colorectal cancer. Oncolytic virotherapy is another emerging potential treatment option, especially when combined with standard chemotherapy and/or radiation, as well as immunotherapy. And finally, radioembolization with yttrium-90 (
Y) microspheres has shown some success in treating patients with unresectable liver metastasis from colorectal cancer via selective arterial injection.
Cancer genome sequencing enables accurate classification of tumours and tumour subtypes. However, prediction performance is still limited using exome-only sequencing and for tumour types with low ...somatic mutation burden such as many paediatric tumours. Moreover, the ability to leverage deep representation learning in discovery of tumour entities remains unknown.
We introduce here Mutation-Attention (MuAt), a deep neural network to learn representations of simple and complex somatic alterations for prediction of tumour types and subtypes. In contrast to many previous methods, MuAt utilizes the attention mechanism on individual mutations instead of aggregated mutation counts.
We trained MuAt models on 2587 whole cancer genomes (24 tumour types) from the Pan-Cancer Analysis of Whole Genomes (PCAWG) and 7352 cancer exomes (20 types) from the Cancer Genome Atlas (TCGA). MuAt achieved prediction accuracy of 89% for whole genomes and 64% for whole exomes, and a top-5 accuracy of 97% and 90%, respectively. MuAt models were found to be well-calibrated and perform well in three independent whole cancer genome cohorts with 10,361 tumours in total. We show MuAt to be able to learn clinically and biologically relevant tumour entities including acral melanoma, SHH-activated medulloblastoma, SPOP-associated prostate cancer, microsatellite instability, POLE proofreading deficiency, and MUTYH-associated pancreatic endocrine tumours without these tumour subtypes and subgroups being provided as training labels. Finally, scrunity of MuAt attention matrices revealed both ubiquitous and tumour-type specific patterns of simple and complex somatic mutations.
Integrated representations of somatic alterations learnt by MuAt were able to accurately identify histological tumour types and identify tumour entities, with potential to impact precision cancer medicine.
Recently, there has been a growing interest in the medical applications of
plants. They owe their unique properties to a group of secondary metabolites known as phytocannabinoids, which are specific ...for this genus. Phytocannabinoids, and cannabinoids generally, can interact with cannabinoid receptors being part of the endocannabinoid system present in animals. Over the years a growing body of scientific evidence has been gathered, suggesting that these compounds have therapeutic potential. In this article, we review the classification of cannabinoids, the molecular mechanisms of their interaction with animal cells as well as their potential application in the treatment of human diseases. Specifically, we focus on the research concerning the anticancer potential of cannabinoids in preclinical studies, their possible use in cancer treatment and palliative medicine, as well as their influence on the immune system. We also discuss their potential as therapeutic agents in infectious, autoimmune, and gastrointestinal inflammatory diseases. We postulate that the currently ongoing and future clinical trials should be accompanied by research focused on the cellular and molecular response to cannabinoids and
extracts, which will ultimately allow us to fully understand the mechanism, potency, and safety profile of cannabinoids as single agents and as complementary drugs.
Bone metastasis resulting from advanced breast cancer causes osteolysis and increases mortality in patients. Kalkitoxin (KT), a lipopeptide toxin derived from the marine cyanobacterium
(previously
, ...has an anti-metastatic effect on cancer cells. We verified that KT suppressed cancer cell migration and invasion in vitro and in animal models in the present study. We confirmed that KT suppressed osteoclast-soup-derived MDA-MB-231 cell invasion in vitro and induced osteolysis in a mouse model, possibly enhancing/inhibiting metastasis markers. Furthermore, KT inhibits CXCL5 and CXCR2 expression, suppressing the secondary growth of breast cancer cells on the bone, brain, and lungs. The breast-cancer-induced osteolysis in the mouse model further reveals that KT plays a protective role, judging by micro-computed tomography and immunohistochemistry. We report for the first time the novel suppressive effects of KT on cancer cell migration and invasion in vitro and on MDA-MB-231-induced bone loss in vivo. These results suggest that KT may be a potential therapeutic drug for the treatment of breast cancer metastasis.
Among esophagogastric cancer patients, the probability of having undergone treatment with curative intent has been shown to vary, depending on the hospital of diagnosis. However, little is known ...about the factors that contribute to this variation. In this study, we sought to understand the organization of clinical pathways and their association with variation in practice.
A mixed-method study using quantitative and qualitative data was conducted. Quantitative data were obtained from the Netherlands Cancer Registry (e.g., outpatient clinic consultations and diagnostic procedures). For qualitative data, thematic content analysis was performed using semi-structured interviews (n = 30), observations of outpatient clinic consultations (n = 26), and multidisciplinary team meetings (MDTM, n = 16) in eight hospitals, to assess clinicians' perspectives regarding the clinical pathways.
Quantitative analyses showed that patients more often underwent surgical consultation prior to the MDTM in hospitals associated with a high probability of receiving treatment with curative intent, but more often consulted with a geriatrician in hospitals associated with a low probability of such treatment. The organization of clinical pathways was analyzed quantitatively at three levels: regional, local, and patient levels. At a regional level, hospitals differed in terms of the number of patients discussed during the MDTM. At the local level, the revision of radiological images and restaging after neoadjuvant treatment varied. At the patient level, some hospitals routinely conduct fitness tests, whereas others estimated the patient's physical fitness during an outpatient clinic consultation. Few clinicians performed a standard geriatric consultation in older patients to assess their mental fitness and frailty.
Surgical consultation prior to MDTM was more often conducted in hospitals associated with a high probability of receiving treatment with curative intent, whereas a geriatrician was consulted more often in hospitals associated with a low probability of receiving such treatment.
Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient ...population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time.
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