Cancer Therapies Provoke Wide Range of Skin Effects

Ubiquilins or UBQLNs, members of the ubiquitin-like and ubiquitin-associated domain (UBL-UBA) protein family, serve as adaptors to coordinate the degradation of specific substrates via both proteasome and autophagy pathways. The UBQLN substrates reveal great diversity and impact a wide range of cellular functions. For decades, researchers have been attempting to uncover a puzzle and understand the role of UBQLNs in human cancers, particularly in the modulation of oncogene’s stability and nucleotide excision repair. In this review, we summarize the UBQLNs’ genetic variants that are associated with the most common cancers and also discuss their reliability as a prognostic marker. Moreover, we provide an overview of the UBQLNs networks that are relevant to cancers in different ways, including cell cycle, apoptosis, epithelial-mesenchymal transition, DNA repairs and miRNAs. Finally, we include a future prospective on novel ubiquilin-based cancer therapies.

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Early Tumor Detection Using Platelet Uptake of Angiogenesis Regulators.

Blood ◽

10.1182/blood.v104.11.839.839 ◽

2004 ◽

Vol 104 (11) ◽

pp. 839-839 ◽

Cited By ~ 18

Author(s):

Giannoula Klement ◽

Lena Kikuchi ◽

Mark Kieran ◽

Nava Almog ◽

Tai-Tung Yip ◽

...

Keyword(s):

Human Tumor ◽

Human Platelets ◽

Cancer Therapies ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Platelet Surface ◽

Wide Range ◽

Anti Cancer ◽

Early Tumor ◽

Tumor Types

Abstract We report a new function for platelets: selective sequestration of tumor-derived angiogenesis regulatory proteins above the concentration of these molecules in plasma. Iodinated VEGF in a Matrigel pellet (from 100 to 600 ng/100 microl), implanted subcutaneously in mice, accumulates almost exclusively in platelets in a dose-dependent manner over a period as long as 2–3 weeks, without raising plasma levels of VEGF. Similarly, platelet VEGF increases in the presence of a single microscopic VEGF-secreting human tumor of up to only 1 mm3 in SCID mice without any increase of VEGF in plasma. In addition to VEGF, other factors such as bFGF, PDGF, BDNF, endostatin and other regulators of angiogenesis are taken up by platelets in a selective and quantifiable manner which is dependent on tumor generation of these molecules. Our data show that these proteins are not simply associated with the platelet surface, but are internalized. Furthermore, they are protected from degradation within the platelet, and are not released by classical degranulating agents, such as thrombin, ADP or epinephrine. Incubation of human platelets with endostatin at above physiological levels results in decrease of the majority of platelet-associated VEGF and bFGF in a concentration-dependent manner. Using SELDI-ToF mass spectroscopy of platelet extracts, we have found that this novel property of platelets enables the detection of microscopic tumors that undetectable by any presently available diagnostic method. The platelet angiogenic profile is more inclusive than a single biomarker because it can detect a wide range of tumor types and tumor sizes. Relative changes in the platelet angiogenic profile permit the tracking of a tumor throughout its development, beginning from an early in situ cancer. Conclusions: (i) While the half-life of mouse platelets is approximately 3 days, the platelet angiogenic profile persists for as long as the tumor (or Matrigel pellet) is present. This indicates that platelets may continuously scavenge proteins which regulate angiogenesis. (ii) The fact that the presence of a human tumor can now be detected at microscopic size, suggests that it may not be necessary to know the type and location of a tumor before initiating treatment, especially since it is feasible to use anti-cancer therapies of little or no toxicity. Figure Figure

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Idronoxil as an Anticancer Agent: Activity and Mechanisms

Current Cancer Drug Targets ◽

10.2174/1568009620666200102122830 ◽

2020 ◽

Vol 20 (5) ◽

pp. 341-354 ◽

Cited By ~ 2

Author(s):

Kate Porter ◽

Walter Douglas Fairlie ◽

Olivier Laczka ◽

Frederic Delebecque ◽

John Wilkinson

Keyword(s):

Biological Effects ◽

Cancer Therapies ◽

Cellular Targets ◽

The Past ◽

Cycle Arrest ◽

Anticancer Effects ◽

Wide Range ◽

Inhibition Of Angiogenesis ◽

The Subject ◽

Second Chance

Idronoxil has been the subject of more than 50 peer-reviewed publications over the last two decades. This isoflavone is an intriguing regulator of multiple signal transduction pathways, capable of causing a range of biological effects, including cell cycle arrest, apoptosis, an ability to stimulate the immune system, and inhibition of angiogenesis. These multifaceted actions suggest that idronoxil has the potential to synergize with, or complement, a wide range of cancer therapies. Whilst clinically tested in the past, idronoxil’s journey was discontinued as a result of its low bioavailability in humans when administered either intravenously or orally, though strategies to overcome this issue are currently being explored. Here, we summarize the current literature regarding the key cellular targets of idronoxil and the mechanisms by which idronoxil exerts its anticancer effects, laying a new foundation toward giving this unique molecule a second chance of contributing to the future of cancer treatment.

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Identification of a Mimicry of the Protein that Potentially Isolates the Mutated p53 Material and Prevents Further Protein Accumulation

10.36811/ojrmi.2021.110024 ◽

2021 ◽

pp. 182-222

Author(s):

Ricardo Gobato ◽

Abhijit Mitra

Keyword(s):

Cancer Cells ◽

P53 Mutation ◽

Lead Author ◽

Protein Accumulation ◽

Cancer Therapies ◽

Protein Mimics ◽

Wide Range ◽

Keywords Cancer ◽

New Cancer Therapies

The team first screened a set of protein mimics originally designed to target Alzheimer's disease and type 2 diabetes. The results identify a mimicry of the protein that potentially isolates the mutated p53 material and prevents further protein accumulation. The researchers then showed that segregation of mutated p53 grains by protein mimicking restored the suppressive function of the p53 tumor, leading to the death of a wide range of cancer cells. Importantly, protein mimicry therapy effectively reduces tumors that contain mutated p53 while showing no significant toxins for healthy tissue, resulting in significantly longer survival. "As the prevalence of cancer increases worldwide, there is an urgent need for new cancer therapies to complement or replace existing therapies," said the study's lead author. Here we show the first successful use of a small molecule amyloid inhibitor as an anticancer agent. We believe that this will have a far-reaching impact, as it effectively bridges the gap between amyloid disease and cancer and is the basis for passing on information approaches in the design of new and robust cancer mutation therapies for the p53 mutation. Keywords: Cancer; Cells; Tissues; Tumors; Prevention; Prognosis; Diagnosis; Imaging; Screening, Treatment; Management

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Patient Derived Models to Study Head and Neck Cancer Radiation Response

Cancers ◽

10.3390/cancers12020419 ◽

2020 ◽

Vol 12 (2) ◽

pp. 419 ◽

Cited By ~ 2

Author(s):

Pippa F. Cosper ◽

Lindsey Abel ◽

Yong-Syu Lee ◽

Cristina Paz ◽

Saakshi Kaushik ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Animal Studies ◽

Model Systems ◽

Mouse Strains ◽

In Vivo Model ◽

Cancer Therapies ◽

Wide Range

Patient-derived model systems are important tools for studying novel anti-cancer therapies. Patient-derived xenografts (PDXs) have gained favor over the last 10 years as newer mouse strains have improved the success rate of establishing PDXs from patient biopsies. PDXs can be engrafted from head and neck cancer (HNC) samples across a wide range of cancer stages, retain the genetic features of their human source, and can be treated with both chemotherapy and radiation, allowing for clinically relevant studies. Not only do PDXs allow for the study of patient tissues in an in vivo model, they can also provide a renewable source of cancer cells for organoid cultures. Herein, we review the uses of HNC patient-derived models for radiation research, including approaches to establishing both orthotopic and heterotopic PDXs, approaches and potential pitfalls to delivering chemotherapy and radiation to these animal models, biological advantages and limitations, and alternatives to animal studies that still use patient-derived tissues.

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GPCR-Hippo Signaling in Cancer

Cells ◽

10.3390/cells8050426 ◽

2019 ◽

Vol 8 (5) ◽

pp. 426 ◽

Cited By ~ 12

Author(s):

Jiaqian Luo ◽

Fa-Xing Yu

Keyword(s):

Cancer Metastasis ◽

Hippo Pathway ◽

Hippo Signaling ◽

Cancer Therapies ◽

Aberrant Expression ◽

Wide Range ◽

Anti Cancer ◽

Genetic Deletion ◽

The Hippo Pathway ◽

G Protein Coupled

The Hippo signaling pathway is involved in tissue size regulation and tumorigenesis. Genetic deletion or aberrant expression of some Hippo pathway genes lead to enhanced cell proliferation, tumorigenesis, and cancer metastasis. Recently, multiple studies have identified a wide range of upstream regulators of the Hippo pathway, including mechanical cues and ligands of G protein-coupled receptors (GPCRs). Through the activation related G proteins and possibly rearrangements of actin cytoskeleton, GPCR signaling can potently modulate the phosphorylation states and activity of YAP and TAZ, two homologous oncogenic transcriptional co-activators, and major effectors of the Hippo pathway. Herein, we summarize the network, regulation, and functions of GPCR-Hippo signaling, and we will also discuss potential anti-cancer therapies targeting GPCR-YAP signaling.

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The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-010919-023340 ◽

2021 ◽

Vol 61 (1) ◽

pp. 541-563 ◽

Cited By ~ 2

Author(s):

Martine J. Smit ◽

Géraldine Schlecht-Louf ◽

Maria Neves ◽

Jelle van den Bor ◽

Petronila Penela ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Chemokine Receptors ◽

Molecular Mechanisms ◽

Cell Types ◽

Cancer Therapies ◽

Signaling Crosstalk ◽

Wide Range ◽

Elevated Expression

Elevated expression of the chemokine receptors CXCR4 and ACKR3 and of their cognate ligand CXCL12 is detected in a wide range of tumors and the tumor microenvironment (TME). Yet, the molecular mechanisms by which the CXCL12/CXCR4/ACKR3 axis contributes to the pathogenesis are complex and not fully understood. To dissect the role of this axis in cancer, we discuss its ability to impinge on canonical and less conventional signaling networks in different cancer cell types; its bidirectional crosstalk, notably with receptor tyrosine kinase (RTK) and other factors present in the TME; and the infiltration of immune cells that supporttumor progression. We discuss current and emerging avenues that target the CXCL12/CXCR4/ACKR3 axis. Coordinately targeting both RTKs and CXCR4/ACKR3 and/or CXCL12 is an attractive approach to consider in multitargeted cancer therapies. In addition, inhibiting infiltrating immune cells or reactivating the immune system along with modulating the CXCL12/CXCR4/ACKR3 axis in the TME has therapeutic promise.

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Patient Derived Models to Study Head and Neck Cancer Radiation Response

10.20944/preprints202001.0218.v2 ◽

2020 ◽

Author(s):

Pippa F. Cosper ◽

Lindsey Abel ◽

Yong-Syu Lee ◽

Cristina Paz ◽

Saakshi Kaushik ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Animal Studies ◽

Model Systems ◽

Mouse Strains ◽

In Vivo Model ◽

Cancer Therapies ◽

Wide Range

Patient derived model systems are important tools for studying novel anti-cancer therapies. Patient derived xenografts (PDXs) have gained favor over the last 10 years as newer mouse strains have improved the success rate of establishing PDXs from patient biopsies. PDXs can be engrafted from head and neck cancer (HNC) samples across a wide range of cancer stages, retain the genetic features of their human source, and can be treated with both chemotherapy and radiation, allowing for clinically relevant studies. Not only do PDXs allow for study of patient tissues in an in vivo model, they can also provide a renewable source of cancer cells for organoid cultures. Herein, we review the uses of HNC patient derived models for radiation research including approaches to establishing both orthotopic and heterotopic PDXs, approaches and potential pitfalls to delivering chemotherapy and radiation to these animal models, biological advantages and limitations, and alternatives to animal studies that still use patient-derived tissues.

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Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Open Biology ◽

10.1098/rsob.210125 ◽

2021 ◽

Vol 11 (11) ◽

Author(s):

Betheney R. Pennycook ◽

Alexis R. Barr

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Mechanism Of Action ◽

Quantitative Imaging ◽

Cancer Therapies ◽

Cycle Arrest ◽

Wide Range ◽

Cast Doubt ◽

A Cell ◽

G1 Cell Cycle Arrest

The use of CDK4/6 inhibitors in the treatment of a wide range of cancers is an area of ongoing investigation. Despite their increasing clinical use, there is limited understanding of the determinants of sensitivity and resistance to these drugs. Recent data have cast doubt on how CDK4/6 inhibitors arrest proliferation, provoking renewed interest in the role(s) of CDK4/6 in driving cell proliferation. As the use of CDK4/6 inhibitors in cancer therapies becomes more prominent, an understanding of their effect on the cell cycle becomes more urgent. Here, we investigate the mechanism of action of CDK4/6 inhibitors in promoting cell cycle arrest. Two main models explain how CDK4/6 inhibitors cause G1 cell cycle arrest, which differ in their dependence on the CDK inhibitor proteins p21 and p27. We have used live and fixed single-cell quantitative imaging, with inducible degradation systems, to address the roles of p21 and p27 in the mechanism of action of CDK4/6 inhibitors. We find that CDK4/6 inhibitors can initiate and maintain a cell cycle arrest without p21 or p27. This work clarifies our current understanding of the mechanism of action of CDK4/6 inhibitors and has implications for cancer treatment and patient stratification.

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Biomarker Tests for Molecularly Targeted Therapies: Laying the Foundation and Fulfilling the Dream

Journal of Clinical Oncology ◽

10.1200/jco.2016.67.3160 ◽

2016 ◽

Vol 34 (17) ◽

pp. 2061-2066 ◽

Cited By ~ 12

Author(s):

Gary H. Lyman ◽

Harold L. Moses

Keyword(s):

Patient Care ◽

Clinical Outcomes ◽

Targeted Therapies ◽

Large Scale ◽

Relevant Literature ◽

Final Report ◽

Cancer Therapies ◽

Institute Of Medicine ◽

Regulatory Oversight ◽

Wide Range

Precision medicine focuses on the management of individual patients on the basis of biomarkers and other distinguishing characteristics, with the overarching objective of improving clinical outcomes. The rapid proliferation of biomarker tests and targeted therapies has revolutionized patient care in a variety of serious disorders. Targeted cancer therapies interrupt oncogenic molecular pathways driven by mutations, overexpression, or translocation of specific genes. However, there is concern that the emergence of large-scale genomic data is exceeding our capacity to appropriately analyze and interpret the results. In 2014, the Institute of Medicine convened the Committee on Policy Issues in the Clinical Development and Use of Biomarkers for Molecularly Targeted Therapies. This committee conducted a study to develop recommendations to address diverse and interconnected development, regulatory, clinical practice, and reimbursement issues. The committee conducted an extensive search of the relevant literature and invited testimony from a wide range of experts in the field. The final report of the committee’s study and deliberations was released on March 4, 2016, focusing on ways to achieve 10 goals to further advance the development and appropriate clinical use of biomarker tests for molecularly targeted therapies. This article presents an overview of the committee’s study and resulting recommendations, which cover establishment of clinical utility, regulatory oversight, coverage and reimbursement, health system data integration, as well as education and access. The committee’s recommendations presented and discussed here are fundamentally grounded in the understanding that, when properly validated and appropriately implemented, these assays and corresponding therapies hold considerable promise to enhance the quality of patient care and improve meaningful clinical outcomes.

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