Improving Prospects for Targeting RAS

2015 ◽  
Vol 33 (31) ◽  
pp. 3650-3659 ◽  
Author(s):  
Harshabad Singh ◽  
Dan L. Longo ◽  
Bruce A. Chabner
Keyword(s):  
Clinical Trials ◽  
Structure Function ◽  
Solid Tumors ◽  
Therapeutic Interventions ◽  
Ras Proteins ◽  
Ras Mutations ◽  
Downstream Signaling ◽  
Synthetically Lethal ◽  
Intense Research ◽  
Ras Inhibitors

RAS mutations are among the most common oncogenic drivers in human cancers, affecting nearly a third of all solid tumors and around a fifth of common myeloid malignancies, but they have evaded therapeutic interventions, despite being the focus of intense research over the last three decades. Recent discoveries lend new understanding about the structure, function, and signaling of RAS and have opened new avenues for development of much needed new therapies. We discuss the various approaches under investigation to target mutant RAS proteins. The recent development of direct RAS inhibitors specific to KRAS G12C mutations represents a landmark discovery that promises to change the perception about RAS's druggability. Multiple clinical trials targeting synthetically lethal partners and/or downstream signaling partners of RAS are underway. Novel inhibitors targeting various arms of RAS processing and signaling have yielded encouraging results in the laboratory, but refinement of the drug-like properties of these molecules is required before they will be ready for the clinic.

scholarly journals Targeting endogenous K-RAS for degradation through the affinity-directed protein missile system

2019 ◽  
Author(s):  
Sascha Röth ◽  
Thomas J. Macartney ◽  
Agnieszka Konopacka ◽  
Markus A. Queisser ◽  
Gopal P. Sapkota
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Specific Inhibitor ◽  
Ubiquitin Proteasome System ◽  
Ras Proteins ◽  
Alternative Therapeutic Approach ◽  
Ubiquitin Proteasome ◽  
Endogenous Proteins ◽  
Missile System ◽  
Ras Inhibitors

AbstractFor over three decades, K-RAS has been known as the holy grail of cancer targets, one of the most frequently mutated oncogenes in cancer. Because the development of conventional small molecule K-RAS inhibitors has been extremely challenging, K-RAS has been dubbed as an undruggable target, and only recently a mutation specific inhibitor has reached clinical trials. Targeted protein degradation has emerged as a new modality in drug discovery to tackle undruggable targets. However, no degrader for K-RAS has been described thus far. Our laboratory has developed an Affinity-directed PROtein Missile (AdPROM) system for targeted proteolysis of endogenous proteins through the ubiquitin proteasome system. Here, we show that we can achieve degradation of endogenous K-RAS and H-RAS in different cell lines in a targeted manner using our AdPROM system. Our findings imply that endogenous RAS proteins can be targeted for proteolysis, thereby offering tantalising possibilities for an alternative therapeutic approach to these so-called undruggable targets in cancer.

scholarly journals Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1260
Author(s):  
Erwan Eriau ◽  
Juliette Paillet ◽  
Guido Kroemer ◽  
Jonathan G. Pol
Keyword(s):  
Clinical Trials ◽  
Caloric Restriction ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
Calorie Intake ◽  
Multiple Model ◽  
Autophagy Induction

Caloric restriction and fasting have been known for a long time for their health- and life-span promoting effects, with coherent observations in multiple model organisms as well as epidemiological and clinical studies. This holds particularly true for cancer. The health-promoting effects of caloric restriction and fasting are mediated at least partly through their cellular effects—chiefly autophagy induction—rather than reduced calorie intake per se. Interestingly, caloric restriction has a differential impact on cancer and healthy cells, due to the atypical metabolic profile of malignant tumors. Caloric restriction mimetics are non-toxic compounds able to mimic the biochemical and physiological effects of caloric restriction including autophagy induction. Caloric restriction and its mimetics induce autophagy to improve the efficacy of some cancer treatments that induce immunogenic cell death (ICD), a type of cellular demise that eventually elicits adaptive antitumor immunity. Caloric restriction and its mimetics also enhance the therapeutic efficacy of chemo-immunotherapies combining ICD-inducing agents with immune checkpoint inhibitors targeting PD-1. Collectively, preclinical data encourage the application of caloric restriction and its mimetics as an adjuvant to immunotherapies. This recommendation is subject to confirmation in additional experimental settings and in clinical trials. In this work, we review the preclinical and clinical evidence in favor of such therapeutic interventions before listing ongoing clinical trials that will shed some light on this subject.

Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials

2018 ◽  
Vol 10 (422) ◽  
pp. eaao0475 ◽  
Author(s):  
Marsha C. Lampi ◽  
Cynthia A. Reinhart-King
Keyword(s):  
Extracellular Matrix ◽  
Clinical Trials ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Therapeutic Interventions ◽  
Target Tissue ◽  
Matrix Stiffness ◽  
Extracellular Matrix Stiffness

Tissues stiffen during aging and during the pathological progression of cancer, fibrosis, and cardiovascular disease. Extracellular matrix stiffness is emerging as a prominent mechanical cue that precedes disease and drives its progression by altering cellular behaviors. Targeting extracellular matrix mechanics, by preventing or reversing tissue stiffening or interrupting the cellular response, is a therapeutic approach with clinical potential. Major drivers of changes to the mechanical properties of the extracellular matrix include phenotypically converted myofibroblasts, transforming growth factor β (TGFβ), and matrix cross-linking. Potential pharmacological interventions to overcome extracellular matrix stiffening are emerging clinically. Aside from targeting stiffening directly, alternative approaches to mitigate the effects of increased matrix stiffness aim to identify and inhibit the downstream cellular response to matrix stiffness. Therapeutic interventions that target tissue stiffening are discussed in the context of their limitations, preclinical drug development efforts, and clinical trials.

Clinical Trials and P Values

PEDIATRICS ◽  
1993 ◽  
Vol 92 (1) ◽  
pp. 189-189
Author(s):  
JOHN D. LANTOS
Keyword(s):  
Clinical Trials ◽  
Patient Care ◽  
Randomized Trials ◽  
Therapeutic Interventions ◽  
P Values ◽  
Clinical Interventions

In Reply.— Here is the question: Are randomized trials so superior to other knowledge-generating techniques that we should not consider a fact to have been established unless it has been established by such a trial? If so, then the use of clinical interventions which have not been studied using randomized trials is wrong. if not, then we need to determine how such trials should be combined with other techniques, and how results of different techniques should be interpreted to lead to the best possible patient care, the incorporation of new therapeutic interventions into practice, and the timely discarding of techniques which are no longer sufficiently efficacious.

scholarly journals Drugging an undruggable pocket on KRAS

2019 ◽  
Vol 116 (32) ◽  
pp. 15823-15829 ◽  
Author(s):  
Dirk Kessler ◽  
Michael Gmachl ◽  
Andreas Mantoulidis ◽  
Laetitia J. Martin ◽  
Andreas Zoephel ◽  
...  
Keyword(s):  
Molecular Switches ◽  
Small Gtpases ◽  
Ras Proteins ◽  
Structure Based Drug Design ◽  
Downstream Signaling ◽  
Activating Mutations ◽  
Ras Genes ◽  
Mutant Cells ◽  
Drug Discovery Target ◽  
Micromolar Range

The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be “undruggable,” between switch I and II on RAS; 1 is mechanistically distinct from covalent KRASG12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS.

scholarly journals Emerging Therapeutic Modalities against COVID-19

2020 ◽  
Vol 13 (8) ◽  
pp. 188 ◽  
Author(s):  
Shipra Malik ◽  
Anisha Gupta ◽  
Xiaobo Zhong ◽  
Theodore P. Rasmussen ◽  
Jose E. Manautou ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Small Molecules ◽  
Therapeutic Interventions ◽  
Pharmaceutical Companies ◽  
The Novel ◽  
Comprehensive Overview ◽  
Therapeutic Modalities ◽  
Academic Researchers ◽  
Approved Drugs ◽  
Fda Approved Drugs

The novel SARS-CoV-2 virus has quickly spread worldwide, bringing the whole world as well as the economy to a standstill. As the world is struggling to minimize the transmission of this devastating disease, several strategies are being actively deployed to develop therapeutic interventions. Pharmaceutical companies and academic researchers are relentlessly working to investigate experimental, repurposed or FDA-approved drugs on a compassionate basis and novel biologics for SARS-CoV-2 prophylaxis and treatment. Presently, a tremendous surge of COVID-19 clinical trials are advancing through different stages. Among currently registered clinical efforts, ~86% are centered on testing small molecules or antibodies either alone or in combination with immunomodulators. The rest ~14% of clinical efforts are aimed at evaluating vaccines and convalescent plasma-based therapies to mitigate the disease's symptoms. This review provides a comprehensive overview of current therapeutic modalities being evaluated against SARS-CoV-2 virus in clinical trials.

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