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Targeted Therapies in Oncology

Release Date: March 3, 2008
Expiration Date: March 3, 2009

Publication Overview

Authors

Davide Melisi,MD; David J. McConkey,Phd

Overview and Purpose

Traditional cytotoxic chemotherapy is believed to kill cancer cells by activation of apoptosis, often as a result of DNA-damage signaling. However, these chemotherapeutic agents also act on normal cells, resulting in toxicities such as myelosuppression. Recent approaches have focused on activating apoptotic pathways specifically in malignant cells. Apoptotic signaling can be initiated by tumor necrosis factorñrelated apoptosis-inducing ligand (TRAIL), which binds to TRAIL receptors 1 and 2; agonistic antibodies to the TRAIL receptors are also in development. Other novel targets include cyclin-dependent kinases, which regulate progression through the cell cycle, Aurora kinases, which ensure proper chromosome separation during mitosis, and poly(ADP-ribose) polymerase-1, which is involved in DNA repair. Agents targeting these molecules are in early-phase clinical trials.

The purpose of this activity is to update physicians on novel targets for anticancer approaches including death receptors, cell-cycle proteins, and DNA repair enzymes.

Target Audience

This activity is intended for medical oncologists involved in the care of patients with solid tumors. No specific skills or knowledge other than a basic training in oncology are required for successful participation in this activity.

Learning Objectives

Upon completion of this educational activity, you should be able to:
  • Discuss the rationale for and current data regarding agents targeting the death receptors in anticancer therapy
  • Discuss the rationale for targeting components of the cell cycle and DNA repair machinery in anticancer therapy
  • Assess the efficacy and safety of novel agents targeting the cell cycle and DNA repair pathways in advanced malignancies

    • Instructions for Participation

    1. Read the following information before beginning the educational activity.
    2. Study the educational activity.
    3. Complete the CME test.
    4. Answer the evaluation questions.
    5. After successful completion of the test and evaluation, you will receive your certificate of credit online.
    • CME credit will be granted for only 1 form of participation, either online or via the printed publication.

    Read all of the conditions in the Activity Terms box below. You must accept the Activity Terms in order to continue:

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    It is the policy of Physicians ’ Education Resource to ensure balance, independence, objectivity, and scientific rigor in all of its educational activities. As an organization accredited by the Accreditation Council for Continuing Medical Education (ACCME), Physicians’ Education Resource requires everyone who is in a position to control the content of an educational activity, including spouses/partners, to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount occurring within the past 12 months that create a conflict of interest. Physicians’ Education Resource has implemented a mechanism to identify and resolve all conflicts of interest prior to the activity.

    David J. McConkey, PhD
    Research Funding ñ AstraZeneca; Nereus Pharmaceuticals; Syndax Pharmaceuticals, Inc.
    Paid Consultant ñ ApoCell, Inc.
    Leadership Position ñ ApoCell, Inc.

    Davide Melisi, MD
    No relevant relationships to disclose

    PER Editorial Staff
    No relevant relationships to disclose

    This CME activity might include discussion of investigational and/or unlabeled uses of drugs. If the activity includes discussion of investigational and/or unlabeled uses of a drug, specific information is located on the first page of the article. Please refer to the full prescribing information for each drug discussed in this activity for FDA-approved dosing, indications, and warnings.

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    Illustration

    The extrinsic pathway is controlled by death receptors and is engaged when they are trimerized by their ligands, as seen with Fas-mediated cell death. The intrinsic pathway is initiated when intracellular stress causes mitochondrial outer membrane permeabilization, resulting in the release of cytochrome c and Smac. Cytochrome c then binds APAF1 and promotes activation of caspase 9, while Smac binds to IAPs and prevents them from binding to and inhibiting caspases 3, 7, and 9. Caspase 8ñmediated cleavage of the BH3-only Bcl-2 family inhibitor Bid results in the translocation of truncated Bcl-2 interacting domain
    to the mitochondria and stimulate release of cytochrome c and Smac, providing coupling between the extrinsic and intrinsic pathways.

    Disclaimer

    The views and opinions expressed in this activity are those of the authors and do not necessarily reflect the views of the sponsor, supporter, or publisher. Although great care has been taken in compiling and checking the information given in this activity to ensure accuracy, the authors and Physicians’ Education Resource and its servants or agents shall not be responsible or in any way liable for the continued currency of the information or for any errors, omissions, or inaccuracies in this activity, whether arising from negligence or otherwise howsoever or for any consequences arising therefrom.

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    Editor, Targeted Therapies in Oncology
    Physicians’ Education Resource
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    Suite 700
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