Jerome Posner, MD

	[Enlarge Image] Figure 1 Examples of nervous system paraneoplastic syndromes

This laboratory studies the biology of paraneoplastic syndromes -- disorders of an organ or tissue caused by cancer, but not a direct effect of the tumor or a metastasis to the involved organ. Neurological paraneoplastic syndromes are defined as disorders of nervous system structure or function caused by a cancer but not ascribable to nervous system metastases or destruction of vital systemic organs by the tumor or treatment.

Paraneoplastic syndromes can affect any portion of the central or peripheral nervous system (Figure 1). Current evidence suggests that most paraneoplastic syndromes are immune-mediated. The hypothesis is that antigens normally expressed only in neurons (or occasionally neurons and testis) are topically expressed in the cancer. The immune system recognizing the antigen in the cancer as foreign mounts an immune attack against the tumor and that portion of the nervous system that expresses the antigen. The result is that the tumors are small, but neurologic symptoms develop.

[Enlarge Image] Figure 2 Paraneoplastic Antigens studied in this lab

Antibodies that react with both the tumor and the nervous system are found in some patients with paraneoplastic syndromes.

This laboratory has identified and characterized some of these antibodies and cloned and sequenced the genes that code for the antigens (Figure 2).

Antibodies characterized in this laboratory are named using the first 2 letters of the last name of the index patient (e.g., anti-Yo -- Figure 3). This figure shows immunohistochemistry and Western blot analysis of a patient with paraneoplastic cerebellar degeneration and ovarian cancer.

The upper left panel demonstrates that the patient's serum reacts with Purkinje cells of the cerebellum but not with other neurons. The panel on the upper right shows that the patient's serum reacts with neoplastic cells from her ovary but not with stromal cells or infiltrating macrophages. The Western blot using extracts of Purkinje cells (middle panel) or extracts of tumor cells (right panel) demonstrates that the patient serum reacts with both, but that normal serum (left panel) does not.

[Enlarge Image] Figure 4 The effect of DNA immunization on growth of the tumor expressing the Hu antigen

In an attempt to characterize the pathophysiology of paraneoplastic syndromes and their possible treatment, we are attempting to develop animal models by immunizing tumor-bearing experimental animals with paraneoplastic protein antigens and their DNA. Passive transfer of antibodies and immunization with protein antigens have thus far not caused neurologic dysfunction.

However DNA immunization has retarded tumor growth in mice expressing the Hu antigen (Figure 4). The figure shows the effect of DNA immunization on growth of the tumor expressing the Hu antigen. Although both protein and DNA immunization caused antibody production, only the DNA inhibited tumor growth. About 15 percent of tumors were rejected after immunization, and the remainder grew more slowly.