Immunoprevention of Breast Ductal Carcinoma in Situ
Abstract
This application addresses the overarching challenge – breast cancer prevention. This proof-of-concept proposal seeks to demonstrate the feasibility of using a vaccine to establish lifelong immunity against the development of breast cancer in women with ductal carcinoma in situ (DCIS) of the breast, a precursor lesion from which invasive disease is thought to evolve. Recently, DCIS is detected more often (>6000 cases each year in the USA alone) due to the implementation of screening programs using mammography. Some of these detected DCIS (about 20%) progress to cancer, while 80% remain indolent or regress and cause no harm to the patients. However, current practice is to remove all DCIS and treat upon diagnosis using surgery and chemotherapy/radiation therapy, whether the DCIS has the potential to progress or not. While this approach results in excellent outcomes in patients with DCIS that have the potential to progress, it overtreats 80% of women. All patients benefited or not from these harsh treatments suffer adverse long-term health effects such as weight gain, fatigue, disfiguring, and depression. Hence, new strategies to prevent cancer development with no long-term adverse effects are urgently needed. Recently, bolstering the patients’ natural immune responses to compact cancer gained some momentum among the scientific community leading to the development of cancer vaccines. Currently, many clinical trials are ongoing using vaccines to treat patients with bulky fast-growing tumors or metastatic disease. However, this approach has not achieved the expected results that the researchers hoped. Vaccines were intended to be prophylactic and used before disease onset or when the tumor burden is small and the patient immune system is robust. However, testing the prophylactic vaccines in patients with no cancer or DCIS is not ethical in addition to long time wait and cost to run such trials. For these reasons, researchers relied on using less than perfect animal models. Although rodent models have yielded promising results, clinical trials in humans, however, have been disappointing. To address the challenges facing prophylactic vaccine development, our laboratory has characterized an animal model that represents human breast cancer faithfully in every aspect. Unlike the rodent model, dogs are immunocompetent and develop mammary cancer spontaneously without any chemical or genetic manipulations. Dogs are outbred than laboratory rodents, yet certain breeds are at increased risk for developing all subtypes (luminal A, luminal B, HER-2, and triple-negative) of mammary tumors. Also, we have found that 50% of randomly screened asymptomatic hound dogs have mammary DCIS and some progress to invasive carcinoma within 1 year. We have shown that canine DCIS lesions, including triple-negative-DCIS (TN-DCIS), resembles human lesions with shared histopathologic and molecular features and with similar imaging and behavioral characteristics. Given the many shared features of canine breast cancer and the high homology between the canine and human genome, the dog model offers an outstanding opportunity for exploiting breast cancer, specifically triple-negative breast cancer (TNBC) immunoprevention strategies. Moreover, the prevalence and rapid progression of canine DCIS provides a much more rapid and cost-effective alternative to human trials for evaluation of the clinical effectiveness of cancer vaccine strategies. Also, our laboratory showed that mammary TN-DCIS-->TNBC progression in dogs displays the expression of tissue-specific self-proteins, alpha-lactalbumin, and mammaglobin A, that are not expressed in immunogenic levels in healthy tissues. These proteins were shown previously to be expressed in human TNBC and are under investigation as neoadjuvant therapeutic vaccines but not as preventative vaccine targets. Given the disappointing results and shortcomings associated with therapeutic vaccine, we hypothesize that vaccination of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110022
Entities
People
- Sulma I Mohammed
Organizations
- Purdue University
- United States Army