Emerging actionable targets to treat therapy-resistant colorectal cancers

Cancer Drug Resistance ◽

10.20517/cdr.2021.96 ◽

2022 ◽

Author(s):

Emanuela Grassilli ◽

Maria Grazia Cerrito

Keyword(s):

Gut Microbiota ◽

Dna Damage Response ◽

Resistance Mechanisms ◽

Therapeutic Approaches ◽

Bcl2 Family ◽

New Therapeutic Approaches ◽

Development Of Resistance ◽

Damage Response ◽

Repair Systems ◽

Resistance To Chemotherapy

In the last two decades major improvements have been reached in the early diagnosis of colorectal cancer (CRC) and, besides chemotherapy, an ampler choice of therapeutic approaches is now available, including targeted and immunotherapy. Despite that, CRC remains a “big killer” mainly due to the development of resistance to therapies, especially when the disease is diagnosed after it is already metastatic. At the same time, our knowledge of the mechanisms underlying resistance has been rapidly expanding which allows the development of novel therapeutic options in order to overcome it. As far as resistance to chemotherapy is concerned, several contributors have been identified such as: intake/efflux systems upregulation; alterations in the DNA damage response, due to defect in the DNA checkpoint and repair systems; dysregulation of the expression of apoptotic/anti-apoptotic members of the BCL2 family; overexpression of oncogenic kinases; the presence of cancer stem cells; and the composition of the tumoral microenvironment and that of the gut microbiota. Interestingly, several mechanisms are also involved in the resistance to targeted and/or immunotherapy. For example, overexpression and/or hyperactivation and/or amplification of oncogenic kinases can sustain resistance to targeted therapy whereas the composition of the gut microbiota, as well as that of the tumoral niche, and defects in DNA repair systems are crucial for determining the response to immunotherapy. In this review we will make an overview of the main resistance mechanisms identified so far and of the new therapeutic approaches to overcome it.

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A Paradigm Shift in the Development of Anti-Candida Drugs

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666191029145209 ◽

2019 ◽

Vol 19 (28) ◽

pp. 2610-2628

Author(s):

D.V. Gowda ◽

M. Afrasim ◽

S.I. Meenakshi ◽

M. Manohar ◽

S. Hemalatha ◽

...

Keyword(s):

Paradigm Shift ◽

Considerable Increase ◽

Antifungal Agents ◽

Resistance Mechanisms ◽

Current Treatment ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Development Of Resistance ◽

Current Treatment Strategy ◽

Candida Infections

Background: The considerable increase in the incidence of Candida infection in recent times has prompted the use of numerous antifungal agents, which has resulted in the development of resistance towards various antifungal agents. With rising Candida infections, the need for design and development of novel antifungal agents is in great demand. However, new therapeutic approaches are very essential in preventing the mortality rate and improving the patient outcome in those suffering from Candida infections. Objective: The present review objective is to describe the burden, types of Candidiasis, mechanism of action of antifungal agents and its resistance and the current novel approaches used to combat candidiasis. Methods: We have collected and analyzed 135 different peer-reviewed literature studies pertinent to candidiasis. In this review, we have compiled the major findings from these studies. Results and Conclusion: The review describes the concerns related to candidiasis, its current treatment strategy, resistance mechanisms and imminent ways to tackle the problem. The review explored that natural plant extracts and essential oils could act as sources of newer therapeutic agents, however, the focus was on novel strategies, such as combinational therapy, new antibodies, utilization of photodynamic therapy and adaptive transfer primed immune cells with emphasis on the development of effective vaccination.

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337 Metabolic Foundations of Microbiota-Host Interactions

Journal of Animal Science ◽

10.1093/jas/skaa278.126 ◽

2020 ◽

Vol 98 (Supplement_4) ◽

pp. 69-69

Author(s):

Dylan Dodd

Keyword(s):

Gastrointestinal Tract ◽

Gut Microbiota ◽

Small Molecules ◽

Recent Work ◽

Mechanistic Studies ◽

Therapeutic Approaches ◽

Dense Population ◽

Metabolic Potential ◽

Host Interactions ◽

New Therapeutic Approaches

Abstract The gastrointestinal tract of mammals is home to a dense population of microbes which influence host physiology and health. One of the most concrete ways that the gut microbiota impacts host biology is through the production of hundreds of chemically diverse small molecules. These molecules are absorbed into the bloodstream, where they reach concentrations similar to those achieved by pharmaceuticals and bind host receptors leading to changes in cellular and organ physiology. Here I will summarize recent work from our group and others that show how microbially sourced metabolites alter health and physiology of the host. I will also discuss how mechanistic studies of small molecules from the microbiota are enabling new therapeutic approaches to harness the metabolic potential of the gut microbiota.

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SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia

Blood ◽

10.1182/blood-2017-03-775569 ◽

2017 ◽

Vol 130 (24) ◽

pp. 2631-2641 ◽

Cited By ~ 46

Author(s):

Brenton G. Mar ◽

S. Haihua Chu ◽

Josephine D. Kahn ◽

Andrei V. Krivtsov ◽

Richard Koche ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Mutation Rate ◽

Histone 3 ◽

Damage Recognition ◽

Key Points ◽

Damage Response ◽

Dna Damage Recognition ◽

Resistance To Chemotherapy

Key Points Alterations of SETD2, a histone 3 lysine 36 trimethyl (H3K36me3) transferase leads to resistance to DNA damaging-chemotherapy in leukemia. Low H3K36me3 levels impair DNA damage response and increase mutation rate, which may be targeted by H3K36me3 demethylase inhibition.

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Gut Microbiota in Canine Idiopathic Epilepsy: Effects of Disease and Treatment

Animals ◽

10.3390/ani11113121 ◽

2021 ◽

Vol 11 (11) ◽

pp. 3121

Author(s):

Sylvia García-Belenguer ◽

Laura Grasa ◽

Olga Valero ◽

Jorge Palacio ◽

Isabel Luño ◽

...

Keyword(s):

Gut Microbiota ◽

Neurological Disorders ◽

Idiopathic Epilepsy ◽

Rrna Gene ◽

Microbiota Composition ◽

Therapeutic Approaches ◽

Faecal Microbiota ◽

New Therapeutic Approaches ◽

Probiotic Intervention ◽

Gut Microbiota Composition

Epilepsy is one of the most common neurological disorders in humans and dogs. The structure and composition of gut microbiome associated to this disorder has not yet been analyzed in depth but there is evidence that suggests a possible influence of gut bacteria in controlling seizures. The aim of this study was to investigate the changes in gut microbiota associated to canine idiopathic epilepsy (IE) and the possible influence of antiepileptic drugs (AEDs) on the modulation of this microbiota. Faecal microbiota composition was analyzed using sequencing of bacterial 16S rRNA gene in a group of healthy controls (n = 12) and a group of epileptic dogs both before (n = 10) and after a 30-day single treatment with phenobarbital or imepitoin (n = 9). Epileptic dogs showed significantly reduced abundance of GABA (Pseudomonadales, Pseudomonadaceae, Pseudomonas and Pseudomona_graminis) and SCFAs-producing bacteria (Peptococcaceae, Ruminococcaceae and Anaerotruncus) as well as bacteria associated with reduced risk for brain disease (Prevotellaceae) than control dogs. The administration of AEDs during 30 days did not modify the gut microbiota composition. These results are expected to contribute to the understanding of canine idiopathic epilepsy and open up the possibility of studying new therapeutic approaches for this disorder, including probiotic intervention to restore gut microbiota in epileptic individuals.

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Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms22158199 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8199

Author(s):

Robert Csaba Kiss ◽

Fen Xia ◽

Scarlett Acklin

Keyword(s):

Dna Damage ◽

Cancer Treatment ◽

Dna Damage Response ◽

Cisplatin Resistance ◽

Therapeutic Index ◽

Resistance Development ◽

Development Of Resistance ◽

Damage Response ◽

Improve Patient ◽

Treatment Personalization

Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe the proteins involved in the pathways and their roles in resistance development. Common biomarkers for cisplatin resistance and their utilization to improve patient risk stratification and treatment personalization are addressed. Finally, we discuss some of the current treatments and future strategies to circumvent the development of cisplatin resistance.

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An Integrated Bioinformatics and Computational Biology Approach Identifies New BH3-Only Protein Candidates

The Open Biology Journal ◽

10.2174/1874196701205010006 ◽

2012 ◽

Vol 5 (1) ◽

pp. 6-16 ◽

Cited By ~ 7

Author(s):

Robert G. Hawley ◽

Yuzhong Chen ◽

Irene Riz ◽

Chen Zeng

Keyword(s):

Dna Damage ◽

Computational Biology ◽

Dna Damage Response ◽

Stress Responses ◽

Response Regulator ◽

Specific Binding ◽

Family Members ◽

Bcl2 Family ◽

A Genome ◽

Damage Response

In this study, we utilized an integrated bioinformatics and computational biology approach in search of new BH3-only proteins belonging to the BCL2 family of apoptotic regulators. The BH3 (BCL2 homology 3) domain mediates specific binding interactions among various BCL2 family members. It is composed of an amphipathic α-helical region of approximately 13 residues that has only a few amino acids that are highly conserved across all members. Using a generalized motif, we performed a genome-wide search for novel BH3-containing proteins in the NCBI Consensus Coding Sequence (CCDS) database. In addition to known pro-apoptotic BH3-only proteins, 197 proteins were recovered that satisfied the search criteria. These were categorized according to α-helical content and predictive binding to BCL-xL (encoded by BCL2L1) and MCL-1, two representative anti-apoptotic BCL2 family members, using position-specific scoring matrix models. Notably, the list is enriched for proteins associated with autophagy as well as a broad spectrum of cellular stress responses such as endoplasmic reticulum stress, oxidative stress, antiviral defense, and the DNA damage response. Several potential novel BH3-containing proteins are highlighted. In particular, the analysis strongly suggests that the apoptosis inhibitor and DNA damage response regulator, AVEN, which was originally isolated as a BCL-xLinteracting protein, is a functional BH3-only protein representing a distinct subclass of BCL2 family members.

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Dysbiosis of gut microbiota in inflammatory bowel disease: Current therapies and potential for microbiota-modulating therapeutic approaches

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2020.5016 ◽

2020 ◽

Author(s):

Dikhnah Alshehri ◽

Omar Saadah ◽

Mahmoud Mosli ◽

Sherif Edris ◽

Rashad Alhindi ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Gut Microbiota ◽

Bowel Disease ◽

Current Treatment ◽

Intestinal Microbiome ◽

Microbiota Composition ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Inflammatory Bowel ◽

Gut Microbiota Composition

There is a growing body of evidence reinforcing the unique connections between the host microbiome, health and diseases. Due to the extreme importance of the symbiotic relationship between the intestinal microbiome and the host, it is not surprising that any alteration in the gut microbiota would result in various diseases, including inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC). IBD is a chronic, relapsing-remitting condition that is associated with significant morbidity, mortality, compromised quality of life and costly medical care. Dysbiosis is believed to exacerbate the progression of IBD. One of the currently used treatments for IBD are anti-tumor necrosis factor (TNF) drugs, representing a biologic therapy that is reported to have an impact on the gut microbiota composition. The efficacy of anti-TNF agents is hindered by the possibility of non-response, which occurs in 10-20% of treated patients, and secondary loss of response, which occurs in up to 30% of treated patients. This underscores the need for novel therapies and studies that evaluate the role of the gut microbiota in these conditions. The success of any therapeutic strategy for IBD depends on our understanding of the interactions that occur between the gut microbiota and the host. In this review, the health and disease IBD-associated microbiota patterns will be discussed, in addition to the effect of currently used therapies for IBD on the gut microbiota composition, as well as new therapeutic approaches that can be used to overcome the current treatment constraints.

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Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

International Journal of Molecular Sciences ◽

10.3390/ijms21072367 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2367 ◽

Cited By ~ 10

Author(s):

Vera Petrova ◽

Ihor Arkhypov ◽

Rebekka Weber ◽

Christopher Groth ◽

Peter Altevogt ◽

...

Keyword(s):

Immune Responses ◽

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Resistance Mechanisms ◽

Cancer Therapies ◽

Effector Cells ◽

Immune Checkpoint Molecules ◽

New Therapeutic Approaches ◽

Development Of Resistance

Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance. These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy. New therapeutic approaches targeting other immune checkpoint molecules are also discussed.

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