scholarly journals The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

2020 ◽  
Author(s):  
Joanna E Zawacka-Pankau
Keyword(s):  
Cancer Therapy ◽  
P53 Protein ◽  
Drug Repurposing ◽  
Standard Of Care ◽  
Tp53 Gene ◽  
Current Standard ◽  
Li Fraumeni Syndrome ◽  
Inherited Cancer ◽  
Human Cancers ◽  
New Treatments

p53 and p73 are critical tumor suppressors often inactivated in human cancers through various mechanisms. Owing to high structural homology, the proteins have many common functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and together with p73 form a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni Syndrome (LFS), the inherited cancer predisposition. In cancers where TP53 gene is intact, p53 is degraded. Despite the ongoing efforts, the treatment of cancers remains challenging. This is due to late diagnoses, the toxicity of current standard of care and marginal benefit of newly approved therapies. Presently, the endeavours focus on reactivating p53 exclusively, neglecting the potential of the restoration of p73 protein for cancer eradication. Taken that several small molecules reactivating p53 failed in clinical trials, there is a need to develop new treatments targeting p53 proteins in cancer. This review outlines the most advanced strategies to reactivate p53 and p73 and describes drug repurposing approaches for the efficient reinstatement of the p53 proteins for cancer therapy.

scholarly journals The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2717
Author(s):  
Joanna E. Zawacka-Pankau
Keyword(s):  
Cancer Therapy ◽  
P53 Protein ◽  
Drug Repurposing ◽  
Standard Of Care ◽  
Tp53 Gene ◽  
Current Standard ◽  
Li Fraumeni Syndrome ◽  
Inherited Cancer ◽  
Human Cancers ◽  
New Treatments

p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and together with p73 forms a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li–Fraumeni syndrome (LFS), the inherited cancer predisposition. In cancers where TP53 gene is intact, p53 is degraded. Despite the ongoing efforts, the treatment of cancers remains challenging. This is due to late diagnoses, the toxicity of the current standard of care and marginal benefit of newly approved therapies. Presently, the endeavors focus on reactivating p53 exclusively, neglecting the potential of the restoration of p73 protein for cancer eradication. Taken that several small molecules reactivating p53 failed in clinical trials, there is a need to develop new treatments targeting p53 proteins in cancer. This review outlines the most advanced strategies to reactivate p53 and p73 and describes drug repurposing approaches for the efficient reinstatement of the p53 proteins for cancer therapy.

scholarly journals The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

2020 ◽  
Author(s):  
Joanna E Zawacka-Pankau
Keyword(s):  
Cancer Therapy ◽  
P53 Protein ◽  
Drug Repurposing ◽  
Protein Family ◽  
Mutant P53 ◽  
Li Fraumeni Syndrome ◽  
Inherited Cancer ◽  
Human Cancers ◽  
New Treatments ◽  
Cycle Regulation

p53 and p73 are critical tumor suppressors inactivated in human cancers through various mechanisms. Owing to high structural homology, the proteins share many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and forms a critical barrier against cancer development and progression. It is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni Syndrome (LFS), the inherited cancer predisposition. Despite the ongoing effort, the treatment of cancers harbouring mutant p53 still remains challenging due to late diagnoses and the treatment-related toxicity and marginal benefit upon approval of new therapies. Presently, the efforts focus on activating p53 exclusively, neglecting the potential of the restoration of the p73 protein in tumors. Taken that several small molecules activating wild-type p53 have failed in clinical trials, and mutant p53 reactivating drugs have not been approved yet, there is a pressing need to develop new treatments activating p53 proteins. This review outlines the still despised therapeutic avenue, drug repurposing, which brings hope for the efficient reinstatement of the p53 protein family for improved cancer therapy.

scholarly journals Novel Treatment Strategies for Glioblastoma

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2883
Author(s):  
Stanley S. Stylli
Keyword(s):  
Median Survival ◽  
Treatment Strategies ◽  
Drug Repurposing ◽  
Standard Of Care ◽  
Invasive Disease ◽  
Central Nervous System Tumor ◽  
Current Standard ◽  
Novel Treatment ◽  
Novel Treatment Strategies ◽  
Molecular Landscape

Glioblastoma (GBM) is the most common primary central nervous system tumor in adults. It is a highly invasive disease, making it difficult to achieve a complete surgical resection, resulting in poor prognosis with a median survival of 12–15 months after diagnosis, and less than 5% of patients survive more than 5 years. Surgical, instrument technology, diagnostic and radio/chemotherapeutic strategies have slowly evolved over time, but this has not translated into significant increases in patient survival. The current standard of care for GBM patients involving surgery, radiotherapy, and concomitant chemotherapy temozolomide (known as the Stupp protocol), has only provided a modest increase of 2.5 months in median survival, since the landmark publication in 2005. There has been considerable effort in recent years to increase our knowledge of the molecular landscape of GBM through advances in technology such as next-generation sequencing, which has led to the stratification of the disease into several genetic subtypes. Current treatments are far from satisfactory, and studies investigating acquired/inherent resistance to current therapies, restricted drug delivery, inter/intra-tumoral heterogeneity, drug repurposing and a tumor immune-evasive environment have been the focus of intense research over recent years. While the clinical advancement of GBM therapeutics has seen limited progression compared to other cancers, developments in novel treatment strategies that are being investigated are displaying encouraging signs for combating this disease. This aim of this editorial is to provide a brief overview of a select number of these novel therapeutic approaches.

scholarly journals GENE-39. CRISPRi-BASED RADIATION MODIFIER SCREEN IDENTIFIES LONG NON-CODING RNA THERAPEUTIC TARGETS IN GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi106-vi106
Author(s):  
S John Liu ◽  
Martina Malatesta ◽  
Kyounghee Seo ◽  
Brian Lien ◽  
Sung Hong ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tumor Growth ◽  
Therapeutic Targets ◽  
Standard Of Care ◽  
Cell Types ◽  
Normal Brain ◽  
Current Standard ◽  
Specific Expression ◽  
Pediatric Glioma ◽  
And Function

Abstract Long noncoding RNAs (lncRNAs) exhibit highly cell type-specific expression and function, making this class of transcript attractive for targeted cancer therapy. However, the vast majority of lncRNAs have not been tested as potential therapeutic targets, particularly in the context of currently used cancer therapy. Malignant glioma is rapidly fatal, and ionizing radiation is part of the current standard-of-care used to slow tumor growth in both adult and pediatric patients. Here, we used a CRISPR interference (CRISPRi) platform to systematically screen 5689 lncRNA loci in human glioblastoma (GBM) cells, identifying 467 hits that modified cell growth in the presence of clinically relevant doses of fractionated radiation. 34 of these lncRNA hits sensitized cells to radiation, and based on their expression in adult and pediatric glioma, nine of these hits were prioritized as lncRNA Glioma Radiation Sensitizers (lncGRS). Knockdown of lncGRS-1 – a primate-conserved, nuclear-enriched lncRNA – inhibited the growth and proliferation of primary adult and pediatric glioma cells, but not the viability of normal brain cells. Using human brain organoids comprised of mature neural cell types as a 3-dimensional tissue substrate to model the invasive growth of glioma, we found that antisense oligonucleotides (ASOs) targeting lncGRS-1 selectively decreased tumor growth synergistically with radiation therapy. These studies identify lncGRS-1 as a glioma-specific therapeutic target and establish a generalizable approach to rapidly identify novel therapeutic targets in the vast non-coding genome that can enhance the standard-of-care for cancer therapy.

Drug Repurposing for Retinoblastoma: Recent Advances

2019 ◽  
Vol 19 (17) ◽  
pp. 1535-1544 ◽  
Author(s):  
Kamakshi Dandu ◽  
Prathap R. Kallamadi ◽  
Suman S. Thakur ◽  
Ch. Mohan Rao
Keyword(s):  
Early Childhood ◽  
Late Effects ◽  
Drug Repurposing ◽  
Standard Of Care ◽  
New Drugs ◽  
Current Standard ◽  
Antiinflammatory Drugs ◽  
Conventional Drug ◽  
Expensive Process ◽  
Calcium Channels Blockers

Retinoblastoma is the intraocular malignancy that occurs during early childhood. The current standard of care includes chemotherapy followed by focal consolidative therapies, and enucleation. Unfortunately, these are associated with many side and late effects. New drugs and/or drug combinations need to be developed for safe and effective treatment. This compelling need stimulated efforts to explore drug repurposing for retinoblastoma. While conventional drug development is a lengthy and expensive process, drug repurposing is a faster, alternate approach, where an existing drug, not meant for treating cancer, can be repurposed to treat retinoblastoma. The present article reviews various attempts to test drugs approved for different purposes such as calcium channels blockers, non-steroidal antiinflammatory drugs, cardenolides, antidiabetic, antibiotics and antimalarial for treating retinoblastoma. It also discusses other promising candidates that could be explored for repurposing for retinoblastoma.

scholarly journals RARE-18. GENETIC EVALUATION IN PATIENTS WITH CHOROID PLEXUS TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii446-iii446
Author(s):  
Milena Oliveira ◽  
Nasjla Silva ◽  
Andrea Cappellano ◽  
Daniela Almeida ◽  
Sergio Cavalheiro ◽  
...  
Keyword(s):  
Family History ◽  
Choroid Plexus ◽  
P53 Protein ◽  
Positive Family History ◽  
Choroid Plexus Papilloma ◽  
Tp53 Gene ◽  
Genetic Evaluation ◽  
Choroid Plexus Tumors ◽  
Li Fraumeni Syndrome ◽  
Plexus Papilloma

Abstract INTRODUCTION Choroid plexus tumors (CPT) are rare intraventricular neoplasms of epithelial origin. They usually occur in the 2nd year of life, corresponding to 0.4–0.6% of intracranial tumors in this age group. They are sub classified, according to WHO 2016, in choroid plexus carcinoma (CPC), atypical choroid plexus papilloma (ACPP) and choroid plexus papilloma (CPP). Li-Fraumeni syndrome (LFS) is present in 50% of patients with CPC. In Brazil, the TP53 p.R337H mutation affects 0.3% of the population in the South/Southeast. OBJECTIVE Evaluate the incidence of genetic mutations in patients with choroid plexus tumors and therefore the importance of genetic evaluation. PATIENTS AND METHODS Between 1992–2019, 38 patients were diagnosed with CPT in our institution, 23 with CPC. From 2012, 21 patients were referred for genetic evaluation, 16 of which had CPC (2 had previously CPP). Positive family history for neoplasms was present in 87.5%; 37.5% compatible with LFS, 50% of them with mutations. All the patients with positive, but unspecific, family history of neoplasms, had pathogenic mutation. The molecular investigation of the TP53 gene in patients with CPC was performed and positive in 56.2%: R337H (5 patients), R110C, R158H, H179R, R196* (1 patient each). Of those with R337H, p53 protein immunohistochemistry resulted in 90–100% positivity. One of the patients with CPP that evolved to CCP had the H179R mutation. Clinical course was similar among them, and with those without mutations. CONCLUSION These results confirm the need for genetic evaluation in patients with choroid plexus tumors for adequate therapeutic management and long-term follow-up.

Drug Repurposing in Human Cancers

2020 ◽  
Vol 27 (42) ◽  
pp. 7213-7213
Author(s):  
Gabriele Grassi ◽  
Mario Grassi
Keyword(s):  
Drug Repurposing ◽  
Human Cancers

Acute Rejection Following Kidney Transplantation: State-of-the-Art and Future Perspectives

2020 ◽  
Vol 26 (28) ◽  
pp. 3468-3496
Author(s):  
Emilio Rodrigo ◽  
Marcio F. Chedid ◽  
David San Segundo ◽  
Juan C.R. San Millán ◽  
Marcos López-Hoyos
Keyword(s):  
Kidney Transplantation ◽  
Acute Rejection ◽  
Rescue Therapy ◽  
Standard Of Care ◽  
Rejection Rate ◽  
New Drugs ◽  
High Dose ◽  
Current Standard ◽  
Antibody Mediated Rejection ◽  
Cellular Rejection

: Although acute renal graft rejection rate has declined in the last years, and because an adequate therapy can improve graft outcome, its therapy remains as one of the most significant challenges for pharmacists and physicians taking care of transplant patients. Due to the lack of evidence highlighted by the available metaanalyses, we performed a narrative review focused on the basic mechanisms and current and future therapies of acute rejection in kidney transplantation. : According to Kidney Disease/Improving Global Outcomes (KDIGO) guidelines, both clinical and subclinical acute rejection episodes should be treated. Usually, high dose steroids and basal immunosuppression optimization are the first line of therapy in treating acute cellular rejection. Rabbit antithymocytic polyclonal globulins are used as rescue therapy for recurrent or steroid-resistant cellular rejection episodes. Current standard-of-care (SOC) therapy for acute antibody-mediated rejection (AbMR) is the combination of plasma exchange with intravenous immunoglobulin (IVIG). Since a significant rate of AbMR does not respond to SOC, different studies have analyzed the role of new drugs such as Rituximab, Bortezomib, Eculizumab and C1 inhibitors. Lack of randomized controlled trials and heterogenicity among performed studies limit obtaining definite conclusions. Data about new direct and indirect B cell and plasma cell depleting agents, proximal and terminal complement blockers, IL-6/IL-6R pathway inhibitors and antibody removal agents, among other promising drugs, are reviewed.

The Molecular Docking of Flavonoids Isolated from Daucus carota as a Dual Inhibitor of MDM2 and MDMX

2020 ◽  
Vol 15 (2) ◽  
pp. 154-164 ◽  
Author(s):  
Ijaz Muhammad ◽  
Noor Rahman ◽  
Gul E. Nayab ◽  
Sadaf Niaz ◽  
Mohibullah Shah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cancer Therapy ◽  
Natural Product ◽  
Signaling Pathway ◽  
In Silico ◽  
P53 Protein ◽  
Dual Inhibitor ◽  
P53 Signaling ◽  
In Silico Studies ◽  
P53 Signaling Pathway

Background: Cancer is characterized by overexpression of p53 associated proteins, which down-regulate P53 signaling pathway. In cancer therapy, p53 activity can be restored by inhibiting the interaction of MDMX (2N0W) and MDM2 (4JGR) proteins with P53 protein. Objective: In the current, study in silico approaches were adapted to use a natural product as a source of cancer therapy. Methods: In the current study in silico approaches were adapted to use a natural product as a source of cancer therapy. For in silico studies, Chemdraw and Molecular Operating Environment were used for structure drawing and molecular docking, respectively. Flavonoids isolated from D. carota were docked with cancerous proteins. Result: Based on the docking score analysis, we found that compound 7 was the potent inhibitor of both cancerous proteins and can be used as a potent molecule for inhibition of 2N0W and 4JGR interaction with p53. Conclusion: Thus the compound 7 can be used for the revival of p53 signaling pathway function however, intensive in vitro and in vivo experiments are required to prove the in silico analysis.

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