Antitumor Activity of Kasugamycin in Primary and Metastatic Lung Cancer
Abstract
Chitinase 3-like 1 (Chi3l1) is a chitin-binding molecule but does not have chitin-degrading enzyme activity. Although humans do not have chitin, Chi3l1 is expressed in blood and various cells and tissues in healthy individuals, and its expression is significantly increased in certain disease conditions such as individuals with infection or malignant tumors. However, the specific role and mechanism that Chi3l1 uses to contribute to the lung cancer development and progression has not been clearly understood. Recent studies from our laboratory demonstrated that Chi3l1 plays a critical role in melanoma lung metastasis, and intervention of Chi3l1 significantly decreased the development and progression of metastatic lung cancer. We identified that Kasugamycin (KSM), an aminoglycoside antibiotic, is a strong chitinase inhibitor that can be used to block Chi3l1 activity. As a preliminary study, we have tested the effects of KSM in melanoma lung metastasis. Surprisingly, we noted that tumor development in the lung was impressively decreased in the mice with KSM treatment compared to vehicle-treated controls. These studies suggest that KSM has a strong anti-tumor activity in the lung. Since tumor-associated macrophages are the major immune cells expressing Chi3l1 and they are known to contribute to tumor development and progression, we hypothesize that KSM inhibits lung cancer development through regulation of Chi3l1-mediated tumor-associated macrophages differentiation. In this proposal, we will test this hypothesis to develop KSM as a potential anti-tumor drug for lung cancer treatment. To achieve this goal, we will first determine the effects of KSM in animal models of primary and metastatic lung cancer (Specific Aim 1). Then we will further define the mechanism that KSM uses to inhibit tumor-associated macrophage development for its anti-tumor activity (Specific Aim 2). The proposed studies align with the following FY21 Primary Focus Areas of Emphasis: (1) Understand the molecular mechanisms of initiation and progression of lung cancer and (2) Identify innovative strategies for lung cancer treatment. Upon successful completion of the proposed studies, we will have KSM as a totally novel, chitinase inhibitor-based, new class of antitumor drug for treatment of lung cancer. Since KSM is an already developed and relatively well-characterized antibiotic with proven low animal toxicity and currently commercially available, it will bring a significant impact on lung cancer treatment in clinical application of KSM alone or in combination with current chemotherapy or immunotherapy. If successful, repurposing KSM as anti-cancer drug will be quickly ready for clinical application. It will also lead to the development of KSM analogues/derivatives for better therapeutic antitumor activity for clinical application to lung cancer patients. Lung cancer is the leading cause of cancers death among both men and women. Since the incidence and the mortality rates from lung cancer in veterans are higher than civilian population, the development of safe and effective therapeutic anti-tumor drug against lung cancer will significantly benefit Veterans and military personnel, as well as civilians.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210101
Entities
People
- Chun Geun Lee
Organizations
- Brown University
- United States Army