scholarly journals Emerging Therapeutic Agents for Colorectal Cancer

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7463
Author(s):  
Marianna Nalli ◽  
Michela Puxeddu ◽  
Giuseppe La Regina ◽  
Stefano Gianni ◽  
Romano Silvestri

There are promising new therapeutic agents for CRC patients, including novel small-molecule inhibitors and immune checkpoint blockers. We focused on emerging CRC’s therapeutic agents that have shown the potential for progress in clinical practice. This review provides an overview of tyrosine kinase inhibitors targeting VEGF and KIT, BRAF and MEK inhibitors, TLR9 agonist, STAT3 inhibitors, and immune checkpoint blockers (PD1/PDL-1 inhibitors), for which recent advances have been reported. These new agents have the potential to provide benefits to CRC patients with unmet medical needs.

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
James Burton ◽  
Sebastian Walpen ◽  
Sandrine Danel ◽  
Lucy Snowdon ◽  
Bernd Schroeppel

Abstract Background and Aims Chronic kidney disease-associated pruritus (CKD-aP) is a common yet under-recognised condition in patients with CKD undergoing haemodialysis (HD), in whom it is associated with reduced health-related quality of life (HRQoL), poor sleep quality, and a greater risk of depression. This real-world study obtained insights from nephrologists in Europe and Australia into the current practices, attitudes and unmet medical needs relating to the diagnosis and treatment of CKD-aP. Method Qualitative data were obtained from structured interviews conducted Oct–Nov 2019 with 72 nephrologists from France, Germany, Italy, Spain, UK and Australia (n=12 in each country). Quantitative data relating to diagnostic/treatment practices for CKD-aP were collected May–July 2020 by a 20-minute physician survey and collection of patient record forms (PRF). The survey was completed by 301 nephrologists from France (n=50), Germany (n=56), Italy (n=58), Spain (n=55), UK (n=52), and Australia (n=30). Respondents’ level of agreement was assessed using a 7-point scale, from 1 (do not agree at all) to 7 (strongly agree). PRF data were also captured for 1435 HD patients with CKD-aP from all countries. All nephrologists who completed the interviews and surveys were currently treating >5 HD patients with CKD-aP. Results Most nephrologists (75%) agreed that CKD-aP is under-diagnosed in HD patients, which is mainly driven by the lack of systematic screening by nephrologists and under-reporting of the condition by patients. The main barriers to screening for CKD-aP identified by nephrologists included the lack of diagnostic guidelines and absence of standardised pruritus intensity scales to consistently diagnose and classify CKD-aP severity. The majority (74%) agreed new clinical guidelines for nephrologists are needed to aid diagnosis. Nephrologists perceived that on average ∼34% of their HD patients experienced CKD-aP, and that 55% of them had moderate-severe symptoms. However, most nephrologists (79%) do not use any itch scales in clinical practice and 71% agreed a consistent international scale to diagnose CKD-aP is needed. 80% of nephrologists agreed diagnosis of CKD-aP is usually patient-driven, indicating there is a reliance on patients mentioning their symptoms. Less than half of nephrologists (46%) agreed that CKD-aP was easy to diagnose by clinical observation alone. The lack of targeted treatment guidelines and approved therapies for CKD-aP leads to an inconsistent, fragmented approach to management. Analysis of prescription data captured in the PRFs of 1435 HD patients with CKD-aP showed treatment in current clinical practice relies on incremental add-on therapy. The majority of patients (∼85-90%) receiving second- or subsequent lines of therapy for CKD-aP were prescribed combinations of different treatments. Commonly prescribed (off-label) medications for CKD-aP included antihistamines, moisturizers/emollients, corticosteroids and gabapentinoids. However, there was no single standard of care for the treatment of CKD-aP, highlighting the uncertainties nephrologists face relating to best treatment practice. Most nephrologists (72%) agreed that treatment options are very limited for patients with bothersome CKD-aP, and the survey responses indicated a high unmet need for novel treatments. The majority of nephrologists felt a major improvement was needed over current treatments, particularly in terms of improved efficacy for reduction of itch intensity (62%) and the ability to improve the patient HRQoL (57%). Conclusion This real-world international survey study of nephrologists showed that CKD-aP is a frequent, but under-diagnosed condition affecting many HD patients, with a lack of effective treatment options. Furthermore, there is an urgent need to develop guidelines to assist in the diagnosis of CKD-aP and new targeted treatment options that are both effective and well tolerated.


Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1408 ◽  
Author(s):  
Pengfei Ye ◽  
Yue Xi ◽  
Zhiying Huang ◽  
Pengfei Xu

The incidence of obesity and colorectal cancer (CRC) has risen rapidly in recent decades. More than 650 million obese and 2 billion overweight individuals are currently living in the world. CRC is the third most common cancer. Obesity is regarded as one of the key environmental risk factors for the pathogenesis of CRC. In the present review, we mainly focus on the epidemiology of obesity and CRC in the world, the United States, and China. We also summarize the molecular mechanisms linking obesity to CRC in different aspects, including nutriology, adipokines and hormones, inflammation, gut microbiota, and bile acids. The unmet medical needs for obesity-related CRC are still remarkable. Understanding the molecular basis of these associations will help develop novel therapeutic targets and approaches for the treatment of obesity-related CRC.


2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Shannon R. Bales ◽  
Inder J. Chopra

The incidence of thyroid cancer is increasing, with a concomitant increase in the number of patients with advanced and metastatic disease. Discoveries regarding the pathogenesis of thyroid cancer have led to the recent development of new therapeutic agents that are beginning to appear on the market. Many of these new agents are targeted kinase inhibitors primarily affecting oncogenic kinases (BRAF V600E, RET/PTC) or signaling kinases (VEGFR, PDGFR). Some of these agents report significant partial response rates, while others attain stabilization of disease as their best response. Their impact on survival is unclear. While these agents target similar pathways, a wide variety of differences exist regarding efficacy and side effect profile. Current expert opinion advises that these agents be used only in a specific subset of patients.


Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5684
Author(s):  
Ernesto Rossi ◽  
Michela Croce ◽  
Francesco Reggiani ◽  
Giovanni Schinzari ◽  
Marianna Ambrosio ◽  
...  

Uveal melanoma (UM) is characterized by relatively few, highly incident molecular alterations and their association with metastatic risk is deeply understood. Nevertheless, this knowledge has so far not led to innovative therapies for the successful treatment of UM metastases or for adjuvant therapy, leaving survival after diagnosis of metastatic UM almost unaltered in decades. The driver mutations of UM, mainly in the G-protein genes GNAQ and GNA11, activate the MAP-kinase pathway as well as the YAP/TAZ pathway. At present, there are no drugs that target the latter and this likely explains the failure of mitogen activated kinase kinase inhibitors. Immune checkpoint blockers, despite the game changing effect in cutaneous melanoma (CM), show only limited effects in UM probably because of the low mutational burden of 0.5 per megabase and the unavailability of antibodies targeting the main immune checkpoint active in UM. The highly pro-tumorigenic microenvironment of UM also contributes to therapy resistance. However, T-cell redirection by a soluble T-cell receptor that is fused to an anti-CD3 single-chain variable fragment, local, liver specific therapy, new immune checkpoint blockers, and YAP/TAZ specific drugs give new hope to repeating the success of innovative therapy obtained for CM.


2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Falko Lange ◽  
Benjamin Franz ◽  
Claudia Maletzki ◽  
Michael Linnebacher ◽  
Maja Hühns ◽  
...  

Low-passage cancer cell lines are versatile tools to study tumor cell biology. Here, we have employed four such cell lines, established from primary tumors of colorectal cancer (CRC) patients, to evaluate effects of the small molecule kinase inhibitors (SMI) vemurafenib, trametinib, perifosine, and regorafenib in anin vitrosetting. The mutantBRAF(V600E/V600K) inhibitor vemurafenib, but also the MEK1/2 inhibitor trametinib efficiently inhibited DNA synthesis, signaling through ERK1/2 and expression of genes downstream of ERK1/2 inBRAFmutant cells only. In case of the AKT inhibitor perifosine, three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant. The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence ofKRAS, BRAF, PIK3CA, andTP53mutations. Regorafenib action was associated with broad-range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK/ERK signaling. In vemurafenib-sensitive cells, the antiproliferative effect of vemurafenib was enhanced by the other SMI. Together, our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low-passage CRC cell lines as preclinical models.


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