Oncolytic Viral Therapies for Soft Tissue Sarcomas
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Questions and Answers

What is the median 5-year survival rate for adult patients with Rhabdomyosarcoma receiving both chemotherapy and radiotherapy?

  • 27%
  • 61%
  • 40%
  • 31% (correct)

What percentage of cancers in children are classified as sarcomas?

  • 7% (correct)
  • 1%
  • 10%
  • 4%

Which type of sarcoma occurs at a higher rate in the population?

  • Soft Tissue Sarcomas (correct)
  • Breast sarcomas
  • Lung sarcomas
  • Bone sarcomas

In which age range does Rhabdomyosarcoma represent 50% of all soft tissue sarcoma tumors?

<p>0-14 years (C)</p> Signup and view all the answers

What is the common response to therapeutic modalities for Rhabdomyosarcoma as indicated by the 10-year disease-free survival rate?

<p>40-41% (A)</p> Signup and view all the answers

Why is treatment for Rhabdomyosarcoma considered inefficient?

<p>Highly metastatic nature and tumor chemoresistance (A)</p> Signup and view all the answers

Which therapeutic approach is cited as one of the best for Rhabdomyosarcoma?

<p>HSV-Tk/GCV suicide gene therapy (B)</p> Signup and view all the answers

What is one of the significant challenges in studying Rhabdomyosarcoma?

<p>Rarity of the tumor and low prevalence (B)</p> Signup and view all the answers

What is the primary role of E1A transcripts in cellular processes?

<p>Inhibit cAMP-mediated transcription (B)</p> Signup and view all the answers

How do E1B proteins interact with p53?

<p>They induce its degradation (B)</p> Signup and view all the answers

What outcome results from the deletion of the E1B-19kDa gene?

<p>Induction of apoptosis in tumorigenic cells (A)</p> Signup and view all the answers

What mechanism does E1B-19kDa use to prevent apoptosis?

<p>Inhibiting Bax/Bak signaling (B)</p> Signup and view all the answers

What effect does the E1B-55 kDa deletion have in p53 dysfunctional cells?

<p>Preferential adenoviral replication (A)</p> Signup and view all the answers

What is the role of P/CAF in relation to E1A?

<p>Is completely inhibited by E1A (A)</p> Signup and view all the answers

In clinical trials, what effect has the combination of E1B-19kDa deleted adenovirus and cisplatin shown?

<p>Higher efficacy in inducing apoptosis (C)</p> Signup and view all the answers

What defines the pro-apoptotic function of E1A transcripts?

<p>Processing procaspase-3 (D)</p> Signup and view all the answers

What is a notable feature of germline p53 mutations in children?

<p>They are frequently detected in rhabdomyosarcoma. (A)</p> Signup and view all the answers

What does the study by Düzgüneş focus on in relation to gene therapy?

<p>Origins of suicide gene therapy. (C)</p> Signup and view all the answers

Which agent is a selective inhibitor for herpes virus replication?

<p>9-(2-hydroxyethoxymethyl)guanine. (C)</p> Signup and view all the answers

Which publication provides information about the response to chemotherapy in adult rhabdomyosarcoma?

<p>Annals of Surgery. (D)</p> Signup and view all the answers

What effect do polymer-coated adenoviruses have as per the research by Fisher et al.?

<p>They allow retargeting and evade neutralizing antibodies. (A)</p> Signup and view all the answers

Which study discusses the adenovirus vector and its modified fibers?

<p>Dmitriev et al. 1998. (D)</p> Signup and view all the answers

Which outcome is linked to the selectivity of action of an antiherpetic agent studied by Elion et al.?

<p>Specific targeting of herpes viruses. (A)</p> Signup and view all the answers

What is the primary focus of the research conducted by Schupak and colleagues regarding soft tissue sarcoma?

<p>Comprehensive understanding and treatment protocols. (C)</p> Signup and view all the answers

What is the primary focus of the database compiled by Sauerbrei and colleagues?

<p>Natural polymorphisms and resistance-related mutations (D)</p> Signup and view all the answers

What is the primary focus of the research conducted by R. Roop in 1995?

<p>Inhibition of melanoma growth (D)</p> Signup and view all the answers

Which type of cancer is specifically analyzed in the work of Shern and colleagues?

<p>Rhabdomyosarcoma (A)</p> Signup and view all the answers

Which adenoviral modification enhances protein product levels for certain transgenes, as noted in the research by Mel Campbell and colleagues?

<p>Incorporation of an arg–gly–asp (rgd) motif (D)</p> Signup and view all the answers

What method was utilized by Smythe and his team in transferring the herpes simplex virus thymidine kinase gene?

<p>Recombinant adenovirus (D)</p> Signup and view all the answers

What was the focus of the publication by Stahlwood and colleagues regarding adenovirus?

<p>Adenovirus infectivity neutralisation by ascitic fluid (C)</p> Signup and view all the answers

What immune response was primarily the subject of the 1999 research by N. Chirmule and colleagues?

<p>Responses to adenoviral vectors (D)</p> Signup and view all the answers

Which treatment method was explored by K. Culver and colleagues in relation to brain tumors?

<p>Retroviral vector-producer cells (C)</p> Signup and view all the answers

What aspect of rhabdomyosarcoma was examined in the study by Sultan and colleagues?

<p>Differences between adult and pediatric cases (A)</p> Signup and view all the answers

Which of the following best describes the type of mutations studied by Sauerbrei and colleagues?

<p>Non-synonymous mutations (C)</p> Signup and view all the answers

What is a significant characteristic of adenoviruses as described by A.J. Davison?

<p>Their genetic content is stable and well-characterized. (C)</p> Signup and view all the answers

Which effect does the fiber knob modification have on adenovirus gene transfer efficiency for human rhabdomyosarcoma cells?

<p>It overcomes low, heterogeneous expression. (A)</p> Signup and view all the answers

Which research area does the publication by Steegenga and colleagues pertain to?

<p>Cellular responses to viral infections (A)</p> Signup and view all the answers

In the 2001 publication by Timothy P. Cripe and colleagues, what limitation of adenovirus gene transfer is addressed?

<p>Low transduction efficiency in certain cell types (B)</p> Signup and view all the answers

What statistical period does Sultan's analysis of rhabdomyosarcoma cases cover?

<p>1973 to 2005 (C)</p> Signup and view all the answers

Which journal featured research on the immune responses to adenoviruses as mentioned in the studies?

<p>Gene Therapy (D)</p> Signup and view all the answers

What plays a crucial role in myoblast fusion during early muscle development?

<p>Connexin43 (Cx43) (B)</p> Signup and view all the answers

What consequence does a reduction in Cx43 expression in breast cancer imply?

<p>Potential role in tumorigenicity (B)</p> Signup and view all the answers

Which connexin is highlighted for its enhanced bystander effect when expressed?

<p>Connexin26 (Cx26) (D)</p> Signup and view all the answers

What is indicated by the heterogeneous distribution of connexins in human malignancy?

<p>Complex functional regulation (D)</p> Signup and view all the answers

What is under investigation to improve therapies like HSVtk/GCV?

<p>Manipulation of connexin expression (B)</p> Signup and view all the answers

What is the proposed function of the recombinant viral vector mentioned?

<p>To phosphorylate GCV and maximize bystander cell transfer (A)</p> Signup and view all the answers

What condition is particularly relevant to disruptions in Cx43 dynamics?

<p>Rhabdomyosarcoma (RMS) (D)</p> Signup and view all the answers

What does the interaction between Pannexin1 (PANX1) and Cx43 suggest?

<p>A complex network influencing RMS malignancy (D)</p> Signup and view all the answers

Flashcards

Sarcomas

A group of cancers that originate from mesenchymal cells, which are cells that develop into connective tissues, such as bone, cartilage, muscle, and fat.

Soft Tissue Sarcomas (STS)

A type of sarcoma that affects the musculoskeletal system, occurring more frequently in children than adults.

Rhabdomyosarcoma (RMS)

The most common and aggressive soft tissue sarcoma in children, representing 50% of all STS tumors in the age range of 0-14 years.

Metastasis

The spread of cancer cells from the primary tumor to other parts of the body.

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Chemoresistance

The ability of cancer cells to resist the effects of chemotherapy drugs.

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Suicide gene therapy

A type of gene therapy that involves inserting a gene that makes a protein that can kill cancer cells.

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HSV-Tk/GCV suicide gene therapy

A type of gene therapy that uses the herpes simplex virus (HSV) to deliver a gene that makes a protein that can kill cancer cells.

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Surgical resection

A common treatment for cancer that involves removing the tumor surgically.

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Rhabdomyosarcoma

A type of cancer that affects the soft tissues of the body, specifically the muscle cells.

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Epithelial Cancer

A type of cancer that affects cells found in the lining of the body's organs and cavities.

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Gene Therapy

The use of a virus to deliver a specific gene to cells.

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Tumor Suppressor Gene

A protein that inhibits the growth of cancerous cells.

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Herpes Simplex Virus (HSV)

A type of virus that causes a skin infection.

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Immune Checkpoint

A protein that activates the immune system.

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Antiviral Medication

A type of medication commonly used to treat viral infections.

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Lymphoma

A type of cancer that develops in the lymphatic system.

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Soft tissue sarcoma

A type of cancer that affects the soft tissues of the body, such as muscles, fat, and nerves.

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p53

A gene that plays a critical role in controlling cell growth and preventing cancer development.

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Adenovirus

A type of virus commonly used as a vector in gene therapy, renowned for its ability to deliver genetic material to cells.

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Acyclovir

A drug that inhibits the replication of the herpes virus, commonly used in the treatment of viral infections.

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Adult Rhabdomyosarcoma

A type of cancer affecting the muscles, known for its potential to affect adults and its response to chemotherapy treatment.

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Cyclin E-cdk2

A protein complex involved in regulating cell growth and development, often disrupted in certain cancers.

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RMS (Rhabdomyosarcoma)

A type of cancer that arises from immature muscle cells, also known as 'rhabdomyosarcoma'.

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Gap junctions

Channels that connect adjacent cells, allowing for communication and transfer of molecules.

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Connexin 43 (Cx43)

A type of connexin protein highly expressed during early muscle development and crucial for myoblast fusion.

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Myogenesis

The process of muscle cell development involving the fusion of individual muscle cells (myoblasts) into multinucleated muscle fibers.

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Bystander effect

A phenomenon where cells indirectly affected by therapy, like those connected through gap junctions, also experience therapeutic effects.

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HSV-1 Tk (Herpes Simplex Virus type 1 Thymidine Kinase)

A viral gene that can be used in therapies to trigger the production of a toxic compound harmful to cancer cells.

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GCV (Ganciclovir)

A type of drug used in cancer therapy, which becomes toxic after being processed by the HSV-1 Tk gene.

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Pannexin 1 (PANX1)

A type of protein that forms large channels in cell membranes, allowing the passage of ions and small molecules.

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E1A transcripts and apoptosis

E1A transcripts promote apoptosis by activating p53, disrupting cell cycle regulation, and inducing caspase-3 processing.

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E1A and p53 activation

E1A interacts with Rb (Retinoblastoma protein) to release E2F, which then promotes transcription of p53.

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E1B transcripts and apoptosis

E1B transcripts are anti-apoptotic; they inhibit p53 activity and prevent apoptosis.

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E1B-55kDa and p53 inhibition

E1B-55kDa, a protein produced by E1B transcripts, binds to p53, disrupts its function, and targets it for degradation.

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E1B-19kDa and mitochondrial pathway

E1B-19kDa inhibits downstream signaling of p53, preventing apoptosis. It acts as a Bcl-2 analogue, inhibiting the mitochondrial pathway.

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Oncolytic adenoviruses and E1B deletions

Deleting E1B-19kDa and 55kDa regions in adenoviruses enhances their oncolytic properties, promoting apoptosis in cancer cells.

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E1B-55kDa deletion and oncolytic specificity

Adenoviruses with E1B-55kDa deleted selectively replicate and spread in cells with dysfunctional p53, showing potential for cancer-targeted treatment.

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Clinical applications of E1B-55kDa deleted adenoviruses

Clinical trials have shown that E1B-55kDa deleted adenoviruses combined with cisplatin are effective in treating advanced squamous cell carcinoma of the head and neck.

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HSV Thymidine Kinase (TK) Gene

A gene that codes for the enzyme thymidine kinase, which is involved in DNA synthesis. It is used in gene therapy to selectively kill cancer cells.

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Adenoviral Vector

A modified adenovirus designed to deliver therapeutic genes more efficiently.

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Coxsackievirus-Adenovirus Receptor (CAR)

A protein found on the surface of many human cells, acting as a receptor for adenoviruses, allowing them to attach and enter cells.

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Complement Receptor 1 (CR1)

A molecule found on the surface of red blood cells that binds to adenoviruses, inhibiting their ability to infect cells.

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Arginine-Glycine-Aspartic Acid Motif (RGD)

A protein sequence comprised of arginine and glycine-aspartic acid, which aids in cell adhesion.

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Immunological Tolerance

A phenomenon where the immune system becomes less responsive to a repeated exposure to the same antigen.

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Study Notes

Comparing Various Oncolytic Viral Therapies with an Optimised HSV-Tk Approach for Soft Tissue Sarcomas

  • This study compares various oncolytic viral therapies for soft tissue sarcomas, focusing on optimizing the HSV-Tk approach, particularly for rhabdomyosarcoma (RMS).

  • Sarcomas are rare mesenchymal tumors, comprising less than 1% of all cancers and 7% of childhood cancers. Rhabdomyosarcoma (RMS) is the most common type, accounting for 50% of soft tissue sarcomas in children aged 0-14.

  • The study investigates the current understanding of the mechanism of GCV-induced apoptosis in HSV-Tk+ cells, highlighting the importance of HSV-1 Tk as the ideal suicide gene, and the need for a viral strain with the highest catalytic activity toward GCV.

  • It examines various delivery vehicles, including lentiviruses, adenoviruses and RNA-based retroviruses, focusing on their viability as vectors for delivering the HSV-Tk gene and determining the ideal choice for RMS-specific gene transduction.

  • The study discusses the role of prodrug choice, specifically ganciclovir (GCV) and its potential for optimization through alteration of its pharmacokinetics, to maximize its efficiency and reduce toxicity.

  • Optimization strategies include the modification of the thymidine kinase (Tk) gene through mutagenesis at specific sites to improve its catalytic activity toward GCV. The use of tumor-specific promoters to limit expression to tumor cells, also increasing specificity and efficacy, and enhancing the bystander effect through connexin transfection.

  • This work examines the effectiveness of different strategies in the context of cancer cell death by apoptosis.

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Biochemistry and Molecular Genetics Library Project Dissertation PDF

Description

This quiz explores the comparison of various oncolytic viral therapies tailored for soft tissue sarcomas, with a special emphasis on the optimized HSV-Tk approach for rhabdomyosarcoma (RMS). Dive into the mechanisms of GCV-induced apoptosis and evaluate the effectiveness of different delivery vehicles in gene therapy.

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