Mark M. Fuster M.D.

Lay Description

Lung cancer is the leading cause of cancer death in the United States and worldwide. Research on the biology of one subtype known as bronchioalveolar carcinoma (BAC) has been limited and challenging, making work toward curative therapies particularly frustrating. “Pure BAC” constitutes 3-5% of lung cancer cases, and typically spreads in a “lepidic” manner throughout airways. Many such patients present with multifocal infiltrates of BAC throughout both lungs, and remain extremely difficult to treat with our limited forms of medical therapy. While this challenging face of BAC remains on the rise, another clinical presentation of BAC is often found as “mixed BAC/ adenocarcinoma,” and in this context it makes up a larger percentage of lung cancers. In addition, this presentation may progress to metastasis and poor prognosis due to the tumor’s propensity to attract blood vessels (a process known as tumor angiogenesis) at focal sites of adenocarcinoma invasion. A strategy that simultaneously blocks the classic airway spread of classic BAC while inhibiting vascular spread by targeting tumor angiogenesis (when it does play a role) may greatly lessen the morbidity and mortality of this disease. We propose a unique combined-treatment strategy that targets both such presentations of BAC in a relatively nontoxic and synergistic manner. Our focus is not on a single molecular pathway; but rather on a strategy that inhibits the activity of multiple growth factors that have been identified as critical for BAC tumor progression while simultaneously blocking the action of a unique group of vascular growth factors involved in stimulating tumor angiogenesis at sites of BAC/ adenocarcinoma invasion.

Proliferation of BAC tumor cells is stimulated by the action of several key growth factor pathways, including activation of the EGF receptor (EGFR) as well as a family of growth factors that depends on the presence of certain complex carbohydrates known as heparan sulfate (HS) proteoglycans on the surface of BAC tumor cells. It turns out that growth of the cells that make up blood capillaries (endothelial cells) in tumors also depends on EGFR signaling as well as the action of a separate family of HS-binding growth factors. Thus, a combined strategy that targets both HS as well as the EGFR pathway in the tumor environment would also limit tumor angiogenesis (where and when it becomes necessary). Our laboratory has experience with both genetic as well as pharmacologic means to inhibit HS in tumor cells as well as endothelial cells. Herein, we propose to examine the effects of blocking EGFR and HS on BAC tumor cells and endothelial cells through genetic and pharmacologic means. We will also examine combined pharmacologic inhibition in BAC/ adenocarcinoma preclinical models. Our hope is to translate such an approach to human BAC as a novel and relatively nontoxic way to block both faces of this disease at multiple levels.

Scientific Abstract

Lung cancer is the leading cause of cancer death in the United States and worldwide. Research on the biology of one subtype known as bronchioalveolar carcinoma (BAC) has been limited and challenging, making work toward curative therapies particularly frustrating. “Pure BAC” constitutes 3-5% of lung cancer cases, and typically spreads in a “lepidic” manner throughout airways. Many such patients present with multifocal infiltrates of BAC throughout both lungs, and remain extremely difficult to treat with our limited forms of medical therapy. While this challenging face of BAC remains on the rise, another clinical presentation of BAC is often found as “mixed BAC/ adenocarcinoma,” and in this context it makes up a larger percentage of lung cancers. In addition, this presentation may progress to metastasis and poor prognosis due to the tumor’s propensity to attract blood vessels (a process known as tumor angiogenesis) at focal sites of adenocarcinoma invasion. A strategy that simultaneously blocks the classic airway spread of classic BAC while inhibiting vascular spread by targeting tumor angiogenesis (when it does play a role) may greatly lessen the morbidity and mortality of this disease. We propose a unique combined-treatment strategy that targets both such presentations of BAC in a relatively nontoxic and synergistic manner. Our focus is not on a single molecular pathway; but rather on a strategy that inhibits the activity of multiple growth factors that have been identified as critical for BAC tumor progression while simultaneously blocking the action of a unique group of vascular growth factors involved in stimulating tumor angiogenesis at sites of BAC/ adenocarcinoma invasion. Proliferation of BAC tumor cells is stimulated by the action of several growth factor pathways, including activation of the EGF receptor (EGFR) as well as a family of growth factors that depends on the presence of certain complex carbohydrates known as heparan sulfate (HS) proteoglycans on the surface of BAC tumor cells. Thus, blockade of EGFR signaling in BAC cells together with a strategy that interferes with the HS carbohydrate molecules themselves would serve to cripple the growth capacity of the BAC tumor mass. It turns out that growth of the cells that make up blood capillaries (endothelial cells) in tumors also depends on EGFR signaling as well as the action of a separate family of HS-binding growth factors. Thus, a combined strategy that targets both HS as well as the EGFR pathway in the tumor environment would also limit tumor angiogenesis (where and when it becomes necessary). Our laboratory has experience with both genetic as well as pharmacologic means to inhibit HS in tumor cells as well as endothelial cells, and we have demonstrated its importance in tumor angiogenesis in preclinical models. Herein, we propose to examine the effects of blocking EGFR and HS on BAC tumor cells and endothelial cells through genetic and pharmacologic means. We will also examine combined pharmacologic inhibition in BAC/ adenocarcinoma preclinical models. Our hope is to translate such an approach to human BAC as a novel and relatively nontoxic way to block both faces of this disease at multiple levels.