Compositions and methods for detecting or eliminating senescent cells to diagnose or treat disease

Abstract

Disclosed are agents (e.g., peptides, polypeptides, proteins, small molecules, antibodies, and antibody fragments that target senescent cells) and methods of their use for imaging senescent cells in vivo and for treating or preventing cancer, age-related disease, tobacco-related disease, or other diseases and disorders related to or caused by cellular senescence in a mammal. The methods include administering one or more of the agents of the invention to a mammal, e.g., a human. The agents, which specifically bind to senescent cells, can be labeled with a radioactive label or a therapeutic label, e.g., a cytotoxic agent.

Description

FIELD OF THE INVENTION[0001]This invention relates to compositions and methods for the detection and treatment of cancer, age-related diseases, tobacco-related diseases, and other diseases and disorders related to or caused by cellular senescence.BACKGROUND OF THE INVENTION[0002]The definition of cellular senescence has undergone some revision since the phenomenon was described by Leonard Hayflick as cessation of replication of cultured human cells after a finite number of population doublings (Hayflick et al., Exp. Cell Res. 37:585-621, 1961). Senescent cells remain metabolically active but do not divide and resist apoptosis for long periods of time (Goldstein, Science 249:1129-1133, 1990). Cellular senescence is characterized by growth cycle arrest in the G1 phase, absence of S phase, and lifespan control by multiple dominant genes (Stanulis-Praeger, Mech. Ageing Dev. 38:1-48, 1987).[0003]Cellular senescence differs from quiescence and terminal differentiation in several important...

AI Technical Summary

Benefits of technology

[0047]By “therapeutic agent” is meant any compound that is used in the detection, diagnosis or treatment of disease. Such compounds may be naturally-occurring, modified, or synthetic. A therapeutic agent may be, for example, an agent that causes apoptosis or necrosis of a cell (e.g., a senescent cell) in an organism (e.g., a mammal, such as a human), thereby reducing the number of such cells in the organism. Therapeutic agents that reduce the number of senescent cells in an organism may be, e.g., alkylating agents, antibiotics, antimetabolites, hormonal agonists or antagonists, anti- or pro-apoptotic agents, immunomodulators, or supplementary potentiating agents.

[0048]By “treating, stabilizing, or preventing cancer” is meant causing a reduction in the size of a tumor or in the number of cancer cells, slowing or preventing an increase in the size of a tumor or in cancer cell proliferation, increasing the disease-free survival time between the disappearance of a tumor or other cancer and its reappearance, preventing an initial or subsequent occurrence of a tumor or other cancer, or reducing an adverse symptom associated with a tumor or other cancer. In a desired embodiment, the percent of tumor or cancerous cells surviving the treatment is at least 20, 40, 60, 80, or 100% lower than the initial number of tumor or cancerous cells, as measured using any standard assay, such as those described herein. Desirably, the decrease in the number of tumor or cancerous cells induced by administration of a compound of the invention is at least 2, 5, 10, 20, or 50-fold greater than the decrease in the number of non-tumor or non-cancerous cells. Desirably, the methods of the present invention result in a decrease of 20, 40, 60, 80, or 100% in the size of a tumor or number of cancerous cells as determined using standard methods. Desirably, at least 20, 40, 60, 80, 90, or 95% of the treated subjects have a complete remission in which all evidence of the tumor or cancer disappears. Desirably, the tumor or cancer does not reappear after more than 5, 10, 15, or 20 years.

Problems solved by technology

Whether replicative senescence actually contributes to aging or age-related symptoms in vivo is questionable on the basis of theoretical estimates of the number of cell divisions that occur in vivo and the absence of strong empirical evidence.

Generally speaking, agents that damage DNA can cause cellular senescence.

This view is supported by experiments in mice showing that p53 knockout results in increased cancer incidence and severity.

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