Key Dates

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

Issued by

National Cancer Institute (NCI)

Purpose

This Notice of Special Interest (NOSI) seeks applications investigating mechanistic and biological aspects of preneoplasia leading to invasive lung and head and neck (HN) cancers. Despite having better molecular understanding of lung and HN cancers and improved therapies for affected patients, these tumors remain a major health problem in the United States (US) and globally. While molecular markers of early injury of the aerodigestive epithelial field have been found, relatively little is known about the molecular mechanisms that initiate these preneoplasias and drive their progression to invasive cancer. In addition, growing evidence highlights the importance of the interaction between the immune system and cancer development. In recent years, immune-based therapies (especially, checkpoint inhibitors) have come to the forefront of standard therapies for many malignancies including lung and HN cancers. However, little is known about the immune regulation of premalignancy, including lung and HN preneoplasias. A functional understanding of the key molecular and cellular changes involved in the formation and advancement of lung and HN preneoplasias will enhance our knowledge of oncogenic progression and accelerate development of effective, rationally designed, preventive and therapeutic strategies.

Background

Lung cancer: Lung cancer continues to be a significant health burden in the United States where over 235,000 new cases are expected in 2021, constituting about 12% of all cancer diagnoses. While the incidence of lung cancer has been declining, the mortality rates (132,000 are estimated for 2021) remain high and lung cancer continues to be a leading cause of cancer deaths in Americans. In general, lung cancers are divided into two groups, non-small cell lung carcinoma (NSCLC), constituting 84% of lung cancers, and small cell lung carcinoma (SCLC), accounting for 13%. NSCLC is composed mainly of two histologic subtypes, adenocarcinoma (AC), which arises in peripheral regions of the lung, and squamous cell carcinoma (SCC), which are found more centrally. Despite the development of novel targeted and immune therapies that have prolonged survival in some NSCLC patients, many patients do not benefit from these therapies and the 5-year survival rate following diagnosis remains poor (21%).

Most lung cancers are attributed to cigarette smoking and all three tumor subtypes (AC, SCC, and SCLC) are commonly found in cigarette smokers. Most lung malignancies are thought to arise from airway epithelia that have been damaged through smoke exposure, an idea termed the airway field of injury. Although this field may appear morphologically normal in smokers, molecular changes have been identified that distinguish it from undamaged lung epithelium from never-smokers. Further damage to the epithelium causes histologic preneoplasias to emerge from this field, as seen in NSCLC, and eventually, invasive carcinomas arise.

Preneoplastic stages have been best defined for SCC where a series of progressive changes have been identified by histopathology. Bronchial hyperplasia and squamous metaplasia are seen first, followed by increasing grades of dysplasia and carcinoma in situ (CIS), after which invasive carcinoma develops. Some molecular alterations have been associated with particular stages of SCC preneoplasia — loss of heterozygosity at chromosomal locus 3p21 in morphologically normal epithelium, p16 methylation in squamous dysplasia, and p53 loss in CIS — suggesting that SCC arises through a multistage progression process. However, not all preneoplasias are destined to progress to invasive cancer and it is not known which molecular changes establish each stage and drive progression.

The preneoplastic states of AC and SCLC are not well understood. In AC, only one preneoplasia type has been identified by histopathology, atypical adenomatous hyperplasia (AAH). Additionally, adenocarcinoma in situ and minimally invasive adenocarcinoma are recognizable histologic entities although their relationship to AAH is not clear. Early molecular alterations in AAH include mutations in K-ras, B-raf, EGFR, and p53. Whether AAH is a requisite step for AC development is not certain. K-ras and EGFR mutations are mutually exclusive in AC, yet some patients with EGFR-mutant AC have concomitant AAH with K-ras mutations present, suggesting that in these cases AC developed via a path distinct from AAH. No clear preneoplasia have been found yet in SCLC and SCLC may arise directly from morphologically normal, damaged epithelium.

Spontaneous regression of some premalignant lesions, including lung lesions, is thought to be, at least in part, immunologically mediated. It is not known what constitutes progressive versus regressive lung preneoplasia. Early studies interrogating gene expression changes and immune marker profiling between normal lung tissue, AAH, and AC show progressive downregulation of genes and pathways involved in anti-tumor T-helper (Th) 1 immunity and upregulation of genes and pathways of pro-tumor Th2 immune responses. Of note, inhibition of anti-tumor signaling (IFN-γ and TGFB1) occurs early in AAH when compared to normal lung tissue.

Head and Neck (HN) Cancer: HN cancer includes tumors that arise from multiple sites, including the oral cavity, pharynx, larynx, paranasal sinuses, and nasal cavity. Most of these tumors are squamous cell carcinomas and are collectively referred to as HNSCC hereafter. In 2021, HNSCC is expected to account for approximately 67,000 new cases and 15,000 deaths in the United States. HNSCCs arising from different primary sites have distinct clinical presentations and outcomes. In general, almost one-third of HNSCCs in humans are diagnosed as a local disease, which is associated with an 85% 5-year survival rate, while tumors diagnosed as regionally advanced and distantly metastatic are associated with survival rates of 67% and 40%, respectively.

While individual subtypes of HNSCC have different etiologies, a common risk factor is tobacco use. Consumption of smokeless tobacco and betel quid, a preparation containing tobacco, is frequently associated with oral cavity HNSCC. Tobacco and alcohol use are implicated in about three-quarters of HNSCCs in humans and heavy consumption of both agents increases risk by 30-fold. Oropharyngeal HNSCC is associated with oral infection by human papillomavirus (HPV). The incidence of HPV-positive oropharyngeal cancers has risen recently in the US whereas the incidence of HPV-negative oral cancer has declined.

HNSCC preneoplasia is not well understood. Like other tobacco-associated malignancies such as lung cancer, HNSCC often arises from the field of injured, normal-appearing epithelium. Approximately 20% of primary HNSCC is associated with a second or subsequent HNSCC. Evidence indicates that multiple oral lesions can arise independently within a field or derive from a single clone that has spread within the epithelium. Because the entire aerodigestive epithelium is exposed to carcinogens from tobacco, HNSCC patients are also at risk for developing second primary tumors at other sites, such as the lung and esophagus. The predominant preneoplastic precursor for HNSCC is dysplasia, although the histopathological characteristics of dysplasia are not predictive of malignant progression or overall prognosis. Molecular studies have identified several common changes in HNSCC dysplasia including chromosomal loss at 9p (CDKN2A), 3p, and 17p (TP53), although the clinical utility of these findings is uncertain. Like the lung, some HN premalignant lesions can regress spontaneously and invasive HNSCC is responsive to immunotherapy with checkpoint inhibitors. However, little is known about the interplay between immunity and development of HN cancer.

Research Objectives

Currently, we have a poor understanding of how lung and HN preneoplasias relate to cancer development. Gaining mechanistic insights into the biology of these preneoplasias and their interplay with the immune system would aid our understanding of how preneoplasias progress or regress. Such knowledge may allow the identification of high-risk individuals who may benefit from surveillance or early intervention and accelerate the development of rationally designed preventive strategies.

Research areas of interest for this NOSI include but are not limited to:

• Understanding mechanistically how the field of injury contributes to lung or HN preneoplasia formation or progression;
• Identifying which lung or HN preneoplasias are benign and which progress, and determining the key molecular and/or cellular factors that govern these outcomes;
• Developing and validating new and human-relevant models of preneoplasia, particularly for HNSCC, SCC, and SCLC, to enable functional characterization of preneoplasia initiation and progression to advanced stages -- model systems could utilize cell, organoid, ex vivo, or whole animal approaches, among others;
• Identifying functional drivers of lung or HN preneoplasia establishment or advancement, particularly genetic and epigenetic changes and immune regulators that determine specific preneoplasia stages or their subsequent progression or regression;
• Understanding the molecular mechanisms that regulate the recognition and removal of preneoplasia;
• Understanding functionally how distinct stromal components, such as immune cells, fibroblasts, and extracellular matrix, contribute to the formation, progression, and/or regression of lung or HN preneoplasia;
• Identifying molecular (including immune) signatures of preneoplasia formation and/or progression that indicate suitability for intervention;
• Finding functional barriers of preneoplasia regression and defining interventional targets to overcome these barriers;
• Understanding how smoking status affects the establishment, progression or regression of lung or HN preneoplasia; and,
• Identifying and developing specific interventions based on functional drivers of preneoplasia progression or barriers of regression.

This NOSI is intended to support discrete, circumscribed projects in lung and HN preneoplasia research. Teams that are interested in a larger concerted effort that combines basic and translational research should consider applying to the Translational and Basic Science Research in Early Lesions (TBEL) funding announcement (NOT-CA-21-060).

Responsiveness

Applications that are responsive to the NOSI include those focused on any areas related to:

• The mechanisms and biology of early and preinvasive stages of lung or HN carcinogenesis;
• Immune regulation of premalignancy at these anatomic sites; and/or
• Identification of potential targets or strategies for early intervention to intercept lung or HN oncogenesis.

Applications that will be considered nonresponsive to this NOSI will include those focused on:

• Advanced disease, such as invasive malignancy (any stage), invasion or metastasis;
• Molecular profiling for biomarker discovery;
• Early detection; and/or
• Clinical trials.

Application and Submission Information:

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcements through the expiration date of this notice.

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

For funding consideration, applicants must include “NOT-CA-21-057” (without quotation marks) in the Agency Routing Identifier field (box 4b) of the SF424 R&R form. Applications without this information in box 4b will not be considered for this initiative.

For NOSIs when the IC is signed on to the target FOA, option 1 below applies. For NOSIs when the IC is not signed on to the target FOA, option 2 below applies.

1. Applications nonresponsive to terms of this NOSI will be not be considered for the NOSI initiative.

2. Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries

Scientific/Research Contact(s)

For applications that relate to cancer biology

Ron Johnson, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6250
Email: rjohnso2@mail.nih.gov

For applications that relate to cancer prevention

Malgorzata (Margaret) Wojtowicz, M.D.
National Cancer Institute (NCI)
Telephone: 240-276-7012
Email: malgorzata.wojtowicz@nih.gov