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Issued by

National Cancer Institute (NCI)

Purpose

The purpose of this Notice of Special Interest (NOSI) is to promote research in understanding the mechanisms by which cannabis and cannabinoids affect cancer biology, cancer interception, cancer treatment and resistance, and management of cancer symptoms.

Background

Usage: The use of cannabis and cannabinoids for medical and recreational purposes has increased dramatically over the past decade. A 2019 survey estimated that 48 million United States (US) individuals aged 12 years or older had used cannabis in the past year, an increase of 87% from a 2002 survey. Within the US, many states have permitted the use of cannabis products, but state policies vary widely regarding the types of products allowed and for what purpose they may be used. Concurrently, the delivery methods of cannabis have diversified and now include edibles, oils, tinctures, topicals and inhaled forms. Cancer patients use cannabis and cannabinoids to manage symptoms of cancer and cancer treatment including anorexia, nausea, and pain. Recent survey evidence suggests that a quarter of cancer patients have used cannabis for symptom management. Despite the increase in cannabis and cannabinoid use, research about their health effects, including potential harms and benefits, remain limited.

Cancer risk: Epidemiological studies of cannabis use and cancer risk have yielded limited and inconsistent results. While cannabis smoke generates many of the same carcinogens as tobacco, studies to date have not shown a link between cannabis smoking and lung cancer risk. There is some evidence suggesting a link of cannabis smoking to increased risk of testicular cancer. However, studies of other cancer types have shown no or inconsistent association with cannabis use, but these data are limited.

Cannabinoid ligands and receptors: Cannabinoids bind to multiple receptors to mediate a range of signaling pathways and cellular responses. Cannabis contains over 60 phytocannabinoids, among which ?⁹-tetrahydrocannabinol (THC), the psychoactive component of cannabis, and cannabidiol (CBD) have been most studied. The classical cannabinoid receptors, CB1 and CB2, are G-protein coupled receptors that inhibit cAMP signaling and can stimulate serine and tyrosine kinase pathways as well. CB1 is expressed highly within the central nervous system and at lower levels in some immune cells while CB2 is abundant in lung, testes and many immune related cells and organs, including macrophages, leukocytes, spleen and thymus. CB1 and CB2 are activated by endogenous lipid-like ligands termed endocannabinoids, which include anandamide and 2-arachidonoylglycerol. Phytocannabinoids and endocannabinoids also bind nonclassical receptors such as G-protein coupled receptors, GPR18 and GPR55, and members of the TRP family of ion channels to modulate a range of cell signaling pathways.

Cancer biology: Endocannabinoid signaling pathways modulate many cancer relevant processes, such as cell proliferation, motility and survival, and often these pathways are dysregulated in cancer. Studies of cannabinoid effects in cancer cell lines and animal models have shown both tumor promoting and tumor suppressive properties. In some animal cancer models, cannabinoid signaling promotes tumorigenesis. For instance, CB2 enhances tumor growth and metastasis in mouse models of HER2-positive breast cancer and THC accelerates growth of HPV-positive head and neck xenograft models. Studies in cancer cell lines indicate that cannabinoid signaling can activate tyrosine kinase pathways such as Src and ERK to promote cell proliferation. However, other cancer models indicate that cannabinoids suppress tumor formation. For example, studies using xenograft mouse models indicate THC inhibits growth of glioblastoma tumors and CBD suppresses prostate tumor growth. Cancer cell line experiments show that THC and CBD can mediate many anti-tumor effects, including inducing apoptosis and inhibiting cell proliferation, invasion and angiogenesis. These anti-tumor activities have led to early clinical testing of THC and CBD for glioblastoma and prostate cancers. While preclinical studies show differing effects of cannabinoids on cancer cells, deeper understanding is needed about how the tumor promoting and suppressive mechanisms of cannabinoid signaling influence cancer biological processes.

Cancer treatment and symptom management: Cancer patients use cannabis and cannabinoids to manage symptoms arising from cancer and cancer treatment such as nausea, appetite, vomiting, cancer-specific pain, and neuropathy. Two synthetic cannabinoids, dronabinol (THC) and nabilone (THC analog), are approved by the Food and Drug Administration to treat symptoms associated with chemotherapy. Increasingly, cancer treatments involve targeted and immunological therapies, but little is known about whether and how cannabis and cannabinoids influence their efficacy. Phytocannabinoids and endocannabinoids affect many cell types of the innate and adaptive immune system to modulate a diverse range of cellular activities including motility, cytokine release, proliferation and cytolytic activation among others. Yet it is not clear whether cannabinoids alter immuno-oncological treatments, such as immune checkpoint treatments and CAR T-cell therapies and by what mechanisms.

Research Objectives

This Notice invites research applications that examine the mechanistic actions of cannabis and cannabinoids in cancer biology, cancer interception, cancer treatment and resistance, and management of cancer symptoms. For this Notice, the relevant forms of cannabinoids for study include both exogenous cannabis, cannabis-derived products or extracts, purified or synthetic cannabinoids, and endogenous cannabinoids.

Areas of research interest include, but are not limited to the following:

• Understanding how exogenous cannabis and cannabinoids affect cancer development (preneoplasia through malignancy) and biology, including the tumor microenvironment;
• Understanding how endogenous cannabinoid pathways influence cancer development and biology;
• Defining the effects of cannabis and cannabinoids on cancer treatment (particularly targeted treatments and immunotherapy) and the development of treatment resistance;
• Understanding the use of cannabis and cannabinoids in cancer interception and delineating how endocannabinoid signaling pathways may inhibit early cancers;
• Defining the mechanisms of cannabis and cannabinoid action in alleviating symptoms of cancer and cancer treatment (such as pain, nausea and neuropathy);
• Understanding the combinatorial effects of cannabis and cannabinoids in conjunction with other factors (such as tobacco constituents, alcohol, microbiome or diet) on cancer biology, treatment and symptom management;
• Identifying biological mechanisms underlying disparities in sex or ethnicity in cannabis and cannabinoid action in cancer biology, treatment or symptom management; and
• Developing or validating new and human-relevant model systems to understand cannabis and cannabinoid action in cancer biology, treatment or symptom management.

Responsiveness

Studies that integrate expertise from multiple disciplines, incorporate state-of-the-art, human-relevant models (e.g., organoid or patient-derived xenograft models) and utilize advanced technologies and methods are strongly encouraged .

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

• Clinical trials;
• Symptoms not related to cancer or cancer treatment;
• Projects that lack cancer models, specimens or cells.

Application and Submission Information

This notice applies to due dates on or after June 5, 2022 and subsequent receipt dates through May 8, 2027.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement 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-22-085 (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.

Although NCI is not listed as a Participating Organization in all the FOAs listed above, applications for this initiative will be accepted.

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
Telephone: 240-276-6250
Email: [email protected]

(For applications that relate to cancer interception)
Sharon Ross, Ph.D., M.P.H.
National Cancer Institute
Telephone: 240-276-7124
Email: [email protected]

(For applications that relate to cancer treatment)
Yali Fu, Ph.D.
National Cancer Institute
Telephone: 240-276-5924
Email: [email protected]

(For applications that relate to cancer symptom management)
Jeffrey White, M.D.
National Cancer Institute
Telephone: 240-276-6595
Email: [email protected]

(For career development (K) applications)
Nastaran Zahir, Ph.D.
National Cancer Institute
Telephone: 240-276-6333
Email: [email protected]

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Carol Perry
National Cancer Institute
Office of Grants Administration
Telephone: 240-276-6282
Email: [email protected]