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FINDING CURES TOGETHER<sup>SM</sup>

AACR-SU2C Research Alerts

New Findings on Metastasis

Title:  "Hepatocytes direct the formation of a pro-metastatic niche in the liver"
SU2C Author:  Gregory L. Beatty, MD, PhD
Grant:  2017 Innovative Research Grant
Published:  Nature; March 6, 2019
DOI:  http://dx.doi.org/10.1038/s41586-019-1004-y

Promising results from the laboratory of SU2C Innovative Research Grant recipient Gregory L. Beatty, MD, PhD, point to possible therapeutic targets for preventing metastasis of pancreatic cancer to the liver.

"The liver is the most common site of metastasis for pancreatic cancer," Dr. Beatty said. "The liver becomes more favorable to metastasis through what we call the formation of a pro-metastatic niche.  Our research indicates the importance of three specific proteins in the process. These findings give us the impetus to explore how we can prevent metastasis by blocking the activity of these proteins."

SUMMARY BY AACR:

The liver is the most common location of cancer metastasis. It is hypothesized that certain conditions develop in the liver that may promote cancer metastasis to this organ. In a paper published by the research group led by SU2C- funded early career investigator, Gregory L. Beatty, MD, PhD, of the University of Pennsylvania, they identified certain proteins that may promote metastasis of pancreatic cancer to the liver. They shared their findings in the journal Nature, the world's most highly cited journal of interdisciplinary science.

In their laboratory experiments, they found that pancreatic cancer cells, and certain normal cells in the tumor microenvironment, produce a protein called interleukin 6 (IL-6). IL-6 affects the liver, inducing the activation of a cellular pathway called STAT3 and consequently, production of a protein called serum amyloid A1 and A2 (SAA). They found that IL6, STAT3, and SAA were critical in promoting changes in the liver that favored metastasis.

Moving from their animal experiments, they looked at patient samples. They observed increased levels of SAA in the blood of pancreatic cancer patients. High levels of circulating SAA seemed to correlate with worse disease outcomes in these patients. Not only did they observe this in pancreatic cancer patients but they also observed increases in SAA in samples from lung cancer and colorectal cancer patients. 

The discovery of the importance of the role of these three proteins: IL-6, STAT3 and SAA, pave the way for designing therapeutics that can prevent pancreatic cancer metastasis to the liver. This is especially critical given that the five-year survival rate for pancreatic cancer drops to a dismal 3 percent once it has metastasized.


New Approach To Pancreatic Cancer

Title:  "Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers"
SU2C Author:  Martin McMahon, PhD
Published:  Nature Medicine, March 4, 2019
DOI:  https://doi.org/10.1038/s41591-019-0367-9

Promising results from the laboratory of Martin McMahon, PhD, at Huntsman Cancer Institute, and in the clinic, demonstrate the therapeutic promise of combining RAF/MEK/ERK inhibitors plus autophagy blockers for the treatment of pancreatic cancer. These data pave the way for a clinical trial funded, in part, by the Pancreatic Cancer Collective.

"Autophagy is an evolutionarily ancient process by which pancreatic cancer cells cannibalize themselves to create building blocks for survival in the face of inhibition of KRAS signaling," said Dr. McMahon. "We have a clinic-ready combination therapy which blocks KRAS signaling plus autophagy leading to tumor cell death. Support of the Pancreatic Cancer Collective is pivotal in allowing us to head into a clinical trial of this intervention."

SUMMARY BY AACR:

The KRAS gene is mutated in more than 80 percent of pancreatic cancers. A critical consequence of this mutation is the overactivation of the proteins RAF, MEK, and ERK. Although this overactivation has been shown to be pivotal in the development of pancreatic cancer, medicines that block these proteins have not been effective as single agents in treating the cancer.

In a paper published by the research group led by Martin McMahon, PhD, of the Huntsman Cancer Institute at the University of Utah, they demonstrate one mechanism by which pancreatic cancer cells evade the effects of RAF/MEK/ERK inhibitors. In the article in the highly rated journal Nature Medicine, the group reported that cells treated with RAF/MEK/ERK inhibitors undergo an increase in autophagy, or the process by which tumor cells recycle their internal contents. This key laboratory observation prompted them to explore whether pancreatic cells can be susceptible to combinations of RAF/MEK/ERK inhibitors and autophagy blockers. Given very promising results from their laboratory and animal experiments, Dr. McMahon's team initiated a clinical trial proposal to test the combination of the MEK inhibitor trametinib and the autophagy inhibitor hydroxychloroquine. A patient with metastatic pancreatic cancer was treated with this combination on a compassionate basis. This patient responded remarkably well.

 Given the potential impact of this new therapeutic strategy, the newly formed Pancreatic Cancer Collective (PCC), the strategic partnership of the Lustgarten Foundation and Stand Up To Cancer, has decided to infuse at least up to $1 million in initial funding to Dr. McMahon's team, via the Collective's New Therapies Challenge grant program. McMahon's work is in line with one of the PCC's objectives: exploring the anticancer potential of medications that are already being used to treat other illnesses.  The two drugs that Dr. McMahon will use – trametinib and hydroxychloroquine – are already being used to treat melanoma and malaria, respectively.

 Supported by this novel grant mechanism, Dr. McMahon will continue developing the MEK/autophagy inhibitor combination strategy through this year. If this therapeutic strategy continues to be promising, Dr. McMahon's team may be eligible for an additional $4 million for an expansion of the study into a larger clinical trial.

 

Glioblastoma: New Findings

Title:  "Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma"
DOI:  http://dx.doi.org/10.1038/s41591-018-0339-5
SU2C Author:  Kurt Schalper, MD, PhD
Title:  "Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma"
DOI:  http://dx.doi.org/10.1038/s41591-019-0349-y
SU2C Author:  Raul Rabadan, PhD
Grants: SU2C Dream Teams:  SU2C-American Cancer Society Lung Cancer Dream Team, SU2C Colorectal Cancer Dream Team (Schalper); NSF/SU2C/V-Foundation Convergence Grant and Phillip A. Sharp Innovation in Collaboration Award (Rabadan)
Published:  Nature Medicine, Feb. 11, 2019
In studying the impact of immunotherapy on glioblastoma, SU2C-funded researchers have identified promising results on the use of the immunotherapy agents called PD-1 inhibitors, as well as clues to the origin of resistance to this class of drugs.

SUMMARY BY AACR:

Glioblastoma is the most common form of brain cancer. Its prognosis remains dismal. Unfortunately, the standard first-line treatment of surgery and chemoradiation has limited efficacy. Immune checkpoint blockade has been a promising therapeutic strategy in many cancers, including melanoma and lung cancer. In light of this, researchers have explored whether immune checkpoint blockade, specifically PD-1 blockade, can also be effective in treating glioblastoma.

SU2C-funded investigators have shared their contribution to this important effort in two research papers in the prestigious journal Nature Medicine.

Kurt Schalper, MD, PhD, and his colleagues studied whether PD-1 inhibitors can also be used to treat glioblastoma patients before they undergo surgery (a treatment regimen called neoadjuvant therapy). Although the number of patients treated was not big enough to make definitive conclusions about the survival benefit of the treatment, they observed that the PD-1 inhibitor induced a more diverse population of the immune cells called T cells at the tumor site.

A more diverse T cell population is a sign of an effective immune system. In light of the positive effects of a PD-1 inhibitor on the immune system even when given as a single-agent and given before surgery, Dr. Schalper's team anticipates that combining anti-PD-1 inhibitors with other immunotherapies can bring us one step closer to effectively treating glioblastoma patients.

Raul Rabadan, PhD, led a team that studied patient samples from 66 glioblastoma patients who were treated with PD-1 inhibitors. They found that patients who did not respond to the treatment had significantly more mutations in the PTEN gene. These mutations may be causing conditions in the tumor microenvironment that keep immune cells from attacking the tumor. Patients who responded to PD-1 inhibitors, on the other hand, had mutations in genes involved in a signaling pathway in the cell known as MAPK. Dr. Rabadan's results, therefore, suggest that it may be beneficial to combine PD-1 inhibitors with targeted drugs against the MAPK pathway.


Nanotechnology in Immunotherapy

Title:  "Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy"
Grant: Stand Up To Cancer Innovative Research Grant (2017)
SU2C Author:  John T. Wilson, PhD
Published: Nature Nanotechnology, Jan. 21, 2019
DOI:  http://dx.doi.org/10.1038/s41565-018-0342-5

An SU2C-supported early career investigator demonstrated the potential of custom-designed nanoparticles to deliver synthetic molecules that can stimulate the body's immune system to fight cancer.  The new technology has the potential to become a new weapon against cancer.

"Nanoparticles potentially can deliver very specific drugs exactly where they are needed most. We hope this research contributes significantly to the development of this exciting new technology," said Dr. Wilson.

SUMMARY BY AACR:

Our bodies utilize a cellular pathway known as STING (stimulator of interferon genes) to mobilize our immune cells to fight cancer. This pathway can be ramped up by using molecules called cGAMP and cyclic dinucleotide (CDN) STING agonists. Unfortunately, these molecules have not been successfully used in the clinic in their native form. With funding from a 2017 SU2C Innovative Research Grant, John T. Wilson, PhD, of Vanderbilt University is studying how cGAMP can be encapsulated inside polymer sacs (referred to as STING-nanoparticles, or STING-NPs) to facilitate their delivery into cells, consequently, activating the STING pathway. He published his progress in the journal Nature Nanotechnology.

Wilson tested the STING-NPs in a mouse model of melanoma. In addition to effectively preventing the growth of the melanoma tumor in a third of the mice, the STING-NPs protected these responding mice from developing tumors even after the mice were no longer receiving the STING-NPs. The STING-NPs can also be combined with immune checkpoint blockade (ICB), and showed potential even in contexts when ICB alone was not effective. These results pave the way to testing whether these STING-NPs can be added to our immune arsenal against 


New Developments in Lung Cancer

Title:  "Early Noninvasive Detection of Response to Targeted Therapy in Non-Small Cell Lung Cancer"
Title:  "Dynamics of tumor and immune responses during immune checkpoint blockade in non-small cell lung cancer"
Grants:  SU2C-American Cancer Society Lung Cancer Dream Team, SU2C-Dutch Cancer Society Dream Team, and SU2C-LUNGevity-American Lung Association Lung Cancer Interception Dream Team.
SU2C Authors:  Jillian Phallen, Patrick M. Forde, Julie R. Brahmer, Valsamo Anagnostou, Edward Gabrielson, Robert B. Scharpf, Victor E. Velculescu
Published: Cancer Research, December 2018

SU2C-funded researchers have developed ways to assess whether drug therapies are working against lung cancer by measuring and analyzing bits of tumor DNA that is circulating in the blood. The analyses can potentially help doctors determine if therapies are working or other treatments should be used.

Summary by AACR: Despite the benefits that have been reaped with targeted therapy and immunotherapy, there remains a need to identify patients who are more likely to respond to these novel strategies. In two papers published in the AACR flagship journal Cancer Research, research groups led by Victor Vesculescu, MD, PhD, of Johns Hopkins University, demonstrated that ultrasensitive measurements and analyses of circulating tumor DNA (ctDNA) can be used to assess response to either targeted therapy (specifically targeted drugs called tyrosine kinase inhibitors or TKIs), or immune checkpoint inhibitors. The research groups are supported in part by three SU2C Dream Team grants: the SU2C-American Cancer Society Lung Cancer Dream Team, the SU2C-Dutch Cancer Society Dream Team, and the SU2C-LUNGevity-American Lung Association Lung Cancer Interception Dream Team.

The researchers obtained blood samples from non-small cell lung cancer patients who were treated with either the TKIs or immune checkpoint blockade. They observed that patient response to immunotherapy can be effectively assessed 8-9 weeks earlier using ctDNA analysis results than by using tumor imaging. Patients whose ctDNA dropped to undetectable levels in response to treatment with immune checkpoint inhibitors survived longer than patients whose ctDNA levels did not decrease.

The researchers also analyzed the sequences of multiple genes in ctDNA and devised a new metric, called cell-free tumor load (cfTL), which takes into account the abundance of the most common sequence alteration in the ctDNA at a particular time point.

The results from Dr. Vesculescu's groups herald that ctDNA assessment can be used as an early predictive tool of a patient's response to immunotherapy and targeted therapy. If these results are confirmed in larger clinical trials, we may see the day when a clinician can use ctDNA levels or ctDNA sequence characteristics to decide sooner if a patient will likely respond or not to immunotherapy or targeted therapy. If there is a low likelihood of response, a patient can be more quickly switched to an alternative therapeutic strategy.


Reactivating Silenced Genes

Title:  "Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer"
Grant:  VARI-SU2C Cancer Epigenetics Dream Team
Authors:  Stephen B. Baylin, Johns Hopkins University, Dream Team Co-leader
Jean-Pierre J. Issa, Temple University, Dream Team Principal
Published:  Cell, Nov. 15, 2018

SU2C-supported scientists found a novel drug class (CDK9 inhibitors) that can reactivate tumor suppressor genes that have been silenced in cancer cells. It is the first time CDK9 has been linked to gene silencing in mammals.

"We have found that targeting CDK9, which is overexpressed in many cancers, can reactivate epigenetically silenced tumor suppressor genes and induce a cellular immune response that may sensitize cancer cells to checkpoint inhibitors." Jean-Pierre J. Issa, MD

Summary by AACR: Cyclin dependent kinases (CDKs) are a family of proteins involved in many cellular processes.  CDK9 regulates transcription, a process in which a section of DNA is copied into RNA by an enzyme called RNA polymerase. In many human cancers, CDK9 is overexpressed, which may lead to rapid proliferation of cancer cells. Researchers supported by SU2C found that inhibiting CDK9 reactivates genes that have been epigenetically silenced by cancer and also enhances the immune response in cells.

The team was led by Jean-Pierre J. Issa, MD, director of the Fels Institute for Cancer Research & Molecular Biology at the Lewis Katz School of Medicine at Temple University in Philadelphia.  The researchers used a drug screening approach to discover a new class of CDK9 inhibitors, including MC180295, which was found to be highly potent and selective in inhibiting CDK9.  Inhibition of CDK9 induced an immune response in cancer cells and sensitized them to another drug called anti-PD1 that is an immune checkpoint inhibitor.