AACR-SU2C Research Alerts
The "stop appetite" hormone may also stop cancer
TITLE: "Oncolytic viruses engineered to enforce leptin expression, reprogram tumor-infiltrating T cell metabolism, and promote tumor clearance"
SU2C Author: Greg M. Delgoffe, PhD
SU2C Grant: Innovative Research Grant (IRG)
Published: Immunity, Aug. 27, 2019
Immunotherapy can be improved to help fight cancer. One strategy is to stimulate T cells by using a hormone that usually signals the brain that the body has had enough to eat.
Summary by the AACR:
There has been great excitement in seeing that our body's defense system called the immune system can be mobilized to kill cancer cells. Unfortunately, the immune cells, especially the cancer-killing T cells, are sometimes incapacitated by metabolic abnormalities.
Greg M. Delgoffe, PhD, is an assistant professor in the University of Pittsburgh Department of Immunology and a 2016 recipient of a Stand Up To Cancer Innovative Research Grant (IRG). In a paper published recently in the journal Immunity, he has helped demonstrate how resolving these metabolic abnormalities can mobilize T cells against cancers like melanoma and pancreatic cancer.
The key to unlocking the potential of T cells is in a hormone called leptin, which normally has a totally different function in the body. It's produced by fat cells, and it communicates to the brain that the body has enough stored fat. Basically, it tells your body when it's time to quit eating. Unfortunately, leptin, as a hormone, cannot be simply taken by patients as a pill. It isn't even effective when injected directly into the tumor. A different delivery system may be in order – such as an oncolytic virus.
This is a type of virus that attacks tumor cells specifically and leaves normal cells alone. When enough of them get into a tumor cell, they can cause it to disintegrate. Bioengineering the virus to secrete leptin is like a double whammy against cancer. The viruses themselves can kill cancer cells. In addition, the leptin that the virus secretes reprograms the metabolism of T cells and enables these immune cells also to attack the cancer cells.
When Delgoffe's team conducted laboratory experiments, the scientists saw that oncolytic viruses by themselves were quite effective in slowing down tumor growth. But oncolytic viruses that were bioengineered to produce leptin were significantly more effective, especially against more aggressive tumors.
These results point to the potential therapeutic benefit of beefing up oncolytic viruses to make them even more effective treatment agents. An oncolytic virus, T-VEC, is already FDA-approved to treat metastatic melanoma. Thus, the work of Delgoffe's team could help lead to additional treatments.
New drug combo looks promising in ovarian cancer
"Single-Arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma"
JAMA Oncology, June 13, 2019
Grant: SU2C-Ovarian Cancer Research Alliance (OCRA)-National Ovarian Cancer Coalition (NOCC) Ovarian Cancer Dream Team
SU2C Authors: Alan D. D'Andrea, Dana-Farber Cancer Institute, Leader
Elizabeth M. Swisher, University of Washington, Co-leader
Ursula A. Matulonis, Dana-Farber Cancer Institute, Investigator
Panagiotis A. Konstantinopoulos, Dana-Farber Cancer Institute, Young Investigator
Women with ovarian cancer who have chemotherapy but suffer recurrence of the disease have limited options for further treatment. A clinical trial shows that a combination of a powerful immunotherapy drug plus a new drug called a PARP inhibitor has encouraging action in ovarian cancer and may open a new avenue for treatment.
Summary by the AACR:
Women with ovarian cancer usually have surgery to remove the tumor or tumors and then chemotherapy combined with other drugs. The chemotherapy most often involves a platinum-based agent. The disease sometimes becomes resistant to the platinum-based therapy, so if the disease comes back, the patient's treatment options are limited. Thus, finding new treatments could potentially help more women survive the disease.
The SU2C-Ovarian Cancer Research Alliance (OCRA)-National Ovarian Cancer Coalition (NOCC) Ovarian Cancer Dream Team was a major supporter of an important clinical trial that tested a new approach to second-line treatment. The team tried out a combination of niraparib (Zejula) and pembrolizumab (Keytruda), drugs that attack cancer cells in different ways.
Niraparib is what is called a PARP inhibitor – a drug that interferes with the process that allows cells to repair damage to the DNA. If enough damage accumulates, the cancer cells can die. The drug was approved by the FDA in 2016.
Pembrolizumab is one of the best-known immunotherapy drugs. It is a "checkpoint inhibitor" that unleashes the immune system to attack and kill cancer cells.
The researchers enrolled 14 patients (nine patients with ovarian cancer and five patients with triple-negative breast cancer) in the phase 1 trial. Fifty-three patients with ovarian cancer were enrolled in the phase 2 portion of the trial. The team published its findings on the integrated analysis for phase 1/2 of 60 ovarian cancer patients in the prestigious journal
Overall, the drug combination was tolerated by the patients and yielded an overall response rate of 18 percet, including 5 percent complete response, 13 percent partial response, 47 percent with stable disease and 33 percent with progressive disease, which the researchers felt were encouraging responses. However, the patient numbers are small, and the team advocates the need for a larger trial to validate the findings. If confirmed, the drug combination could represent a new therapeutic option for women who need a second-line treatment for ovarian cancer.
Lean and stable weight may reduce risk of multiple myeloma
Title: "Elucidating under-studied aspects of the link between obesity and multiple myeloma: Weight pattern, body shape trajectory, and body fat distribution"
Catherine Marinac, PhD, Dana-Farber Cancer Institute; and Timothy R. Rebbeck, PhD, Harvard T.H. Chan School of Public Health
SU2C Grant: SU2C Multiple Myeloma Dream Team
Published: JNCI Cancer Spectrum, June 24, 2019
Maintaining a lean and stable weight throughout life may be of benefit in preventing multiple myeloma.
Summary by the AACR:
Multiple myeloma (MM) is a cancer of the plasma cells that are part of our blood. Obesity has been shown to increase one's risk for developing MM. On the other hand, it has not been clearly shown whether intentionally losing weight or maintaining a specific weight in adulthood can help keep MM at bay.
A team of scientists, including members of the SU2C Multiple Myeloma Dream Team, analyzed weight pattern and multiple myeloma diagnoses data from two famous studies that have followed both female and male health care workers over long periods of time – the Nurses' Health Study, and the Health Professionals Follow-up Study, respectively.
People who had extreme weight cycling – gain and loss of more than 20 pounds – had an increased risk of developing MM when compared to individuals who maintained their weight. In addition, individuals who started with a mid-range body shape and grew larger, had a greater risk of developing MM than those who maintained a lean body shape throughout adulthood.
"Our results suggest that a larger and increasing body shape through age 60 and possibly extreme weight cycling and peripheral adiposity are modifiable risk factors for MM that warrant confirmation in other well-powered prospective studies," the scientists wrote. "Collectively, our findings support the notion that avoiding weight gain by maintaining a lean and stable weight throughout life, particularly beginning early in life, in keeping with public health recommendations, confers the added benefit of MM prevention."
CAR-T cells armed to attack glioblastoma
"CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity"
SU2C Author: Marcela V. Maus, MD, PhD
Grant: Stand Up to Cancer Innovative Research Grant
Published: Nature Biotechnology, July 22, 2019
Although CAR T cells have shown exceptional promise in treatment of blood cancers, they have not been effectively deployed against glioblastoma. Arming CAR T cells with the capability to secrete antibodies called specific bispecific T cell engagers (BiTEs) was shown to significantly increase the anti-glioblastoma efficacy of these cells.
Summary by the AACR:
Tooling up the patient's own immune cells, in a treatment strategy called CAR T cell therapy, has significantly improved outcomes for blood cancer patients. Unfortunately, the same treatment strategy has not been as successful in treating glioblastoma, the deadliest form of brain cancer. Marcela V. Maus, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, and the recipient of an SU2C Innovative Research grant, is working on giving CAR T cells a bigger arsenal with which to fight brain cancer.
CAR T cells are usually designed to home in on a particular protein on the surface of cancer cells. The problem is that a cancer cell may or may not have the protein that the CAR T cell is targeting. Dr. Maus had previously tested a CAR T cell that targeted the mutant form of a cell surface protein called EGFR. When her team tested this CAR T cell in patients, they saw that cells that did not have the mutant protein persisted after the treatment.
In this new paper in the journal
Nature Biotechnology, Maus and her research group describe how they beefed up the CAR T cells by arming them with the ability to secrete antibodies called bispecific T-cell engagers or BiTEs. These BiTEs can enable the T-cells to kill cancer cells that don't have the mutant protein. Not only did the BiTEs synergize with the CAR T cells, but they also activated other T cells which were not originally targeted to the cancer cells.
Laboratory experiments in mice showed that the BiTE-secreting CAR T cells were able to effectively eradicate glioblastoma. These results have the potential of paving the way for treating patients with these BiTE-secreting CAR T cells.
Researchers use "GoT" to focus on blood cancers
"Genotyping of Transcriptomes links somatic mutations and cell identity"
SU2C Author: Dan A. Landau, MD, PhD
Grant: Innovative Research Grant 2016
Published: Nature, July 3, 2019
Scientists integrated genotyping with high-throughput single-cell RNA sequencing to study how mutations can corrupt the formation of blood cells and other blood components and how they contribute to the development of cancers.
"Blood cell development is a complex process whereby stem cells, pass through multiple intermediary stages to give rise to a multitude of mature blood cells," said Dan A. Landau, MD, PhD, Weill Cornell Medicine, a 2016 recipient of an Innovative Research Grant from SU2C. "We
know that malignant mutations disrupt this process to lead to myeloproliferation, but until now, we were not able to study this in patient samples. Our new technology – GoT – allows for the first time to link somatic mutations and cell identity in tens of thousands of single-cells, so that we can study complex processes like blood development, and understand how it corrupted by somatic mutations. This high-resolution mapping of the two superimposed development trajectories – the normal and malignant – helped identify novel potential therapeutic strategies to correct the malignant progression. More broadly, this method will empower cancer researchers to chart directly in patient samples how mutations interact with the cell identity to drive cancer."
Summary by the AACR:
In cancer research, GoT doesn't stand for "Game of Thrones," but it's still an epic struggle as scientists try to unlock mysteries such as how mutations in different cell types within a patient can influence the progression of cancer.
Dr. Landau has developed different tools to characterize individual cells in cancer patients. Understanding how individual cells can morph into cancer and change through treatment can open doors to effectively stopping cancer before it develops and preventing treatment relapse.
In this new paper in
Nature, Landau and a team of researchers developed and used a methodology called GoT (Genotyping of Transcriptomes) to study cells from the bone marrow of patients with a blood cancer called myeloproliferative neoplasms. With GoT, they found that the impact of a particular mutation is not the same across all types of blood cells. The use of GoT enabled them to delineate the importance of multiple mutations in imparting cancerous characteristics to a particular cell.
The software that they used to analyze their GoT data was dubbed "IronThrone."
A source of resistance in colon cancer
"V211D mutation in MEK1 causes resistance to MEK inhibitors in colon cancer"
SU2C Author: Rona Yaeger, MD, Memorial Sloan Kettering Cancer Center
Grant: Stand Up to Cancer Colorectal Cancer Dream Team
Published: Cancer Discovery, June 21, 2019
SU2C-supported researchers are actively testing targeted drugs called MEK inhibitors to treat colorectal cancers with mutations in the
BRAF gene. After identifying a mutation that may keep patients from responding to the drug class, they showed how another type of MEK inhibitor can be used.
Summary by the AACR:
Targeted drugs can be especially effective and less toxic. Because of certain mutations in some colorectal cancers, targeted drugs that block the pro-proliferative MAPK signaling pathway are being actively explored.
Members of the SU2C Colorectal Cancer Dream Team are conducting numerous clinical trials to identify effective treatment strategies for colorectal cancer patients. Rona Yaeger, MD, an investigator on the Dream Team, as part of a clinical trial, is treating colon cancer patients with a MEK inhibitor called binimetinib (MEK is a protein that is part of the MAPK signaling pathway) in combination with another targeted drug, an anti-EGFR antibody, called panitumumab.
In this new paper in AACR's premier journal,
Cancer Discovery, Yaeger and her team share their important finding that can explain why a colorectal cancer patient progressed even when treated with the MEK inhibitor. They identified a new mutation in the cancer cells of this patient. They proceeded to study in the laboratory other drugs that can be used to kill colorectal cancer cells with such a mutation. Their experiments point to the possibility of treating patients who have become resistant to allosteric MEK inhibitors (such as binimetinib), with a different MEK inhibitor drug type (called ATP-competitive inhibitors).
The efforts of the Dream Team underscore the importance of understanding why patients do not respond to a particular treatment, and how this knowledge can help map out new therapeutic strategies.
Organoids Could Guide Personalized Therapy
Title: "Oral mucosal organoids as a potential platform for personalized cancer therapy"
SU2C Author: Hans Clevers, PhD
Grant: SU2C-Dutch Cancer Society Tumor Organoids Dream Team
Published: Cancer Discovery, May 3, 2019
Cell culture models called organoids could potentially be used to find the most effective individualized treatment, such as using drugs or radiotherapy, for patients with head and neck cancers.
Summary by the AACR:
Head and neck cancers are difficult to treat, partly because their location in the body makes surgery complicated, and partly because patient response to treatment has been quite variable. In addition, more than half of the patients relapse even after being treated. Thus, there is a need for reliable methods to help identify the most effective treatments for a particular patient.
The Dream Team co-funded by SU2C and the Dutch Cancer Society has been developing 3D cell culture models called organoids for different cancers. In a recent publication in the premier AACR journal
Cancer Discovery, the team shared its important progress in developing and leveraging head and neck cancer organoids to potentially help guide treatment decisions.
The team grew organoids using surgical resections or biopsies from 31 head and neck cancer patients. They used the genetic information from these organoids to understand why a patient may respond to a particular treatment, or to explore other drugs that may be effective in treating head and neck cancer (even those which are not currently being used to treat this cancer type).
They found that when the organoids had mutations in certain genes –
PIK3CA, KRAS, HRAS or
BRAF – the mutations were resistant to cetuximab, a targeted therapy used in many cases. This information may prompt efforts to screen patients for mutations in these genes before treating these patients with cetuximab to avoid unnecessary treatment.
Head and neck cancer patients can be treated with radiation either before or after surgery, sometimes in combination with chemotherapy. The researchers explored the use of organoids to predict response to radiation. They observed positive indications that the response of the organoids to radiation in the laboratory were similar to the corresponding patient's response to radiotherapy. That is, a patient whose organoids were killed by radiation in the laboratory had a lasting response to radiotherapy. In contrast, patients whose organoids were not killed by radiation in the laboratory, did not respond favorably to radiotherapy. These results strongly suggest that organoids can be used to predict whether a particular patient will be responsive to radiation treatment.
In summary, the team led by Dr. Clevers demonstrated the potential of using head and neck cancer organoids in guiding treatment decisions. We look forward to the day when patients can be exposed to treatment regimens with the highest chances of success and the least toxicity.
Early Warning Signs of Lung Cancer
Title: "Molecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions"
SU2C Authors: Jennifer Beane, PhD; Sarah A. Mazzilli, PhD; Joshua D. Campbell, PhD; Kostyantyn Krysan, PhD; Steven M. Dubinett, MD; Mary E. Reid, PhD; Marc E. Lenburg, PhD; Avrum E. Spira, MD, MSc
Grant: SU2C-LUNGevity-American Lung Association Lung Cancer Interception Dream Team
Published: Nature Communications, April 23, 2019
SU2C scientists working to develop early-warning signs of lung cancer have identified specific types of lesions that, if detected in a patient, can warrant more intensive monitoring or immunoprevention therapy.
"We've discovered some patterns that may indicate which patients are more likely to progress to full-blown lung cancer, which could help guide efforts to intervene at an early stage when the chance of effective treatment is much greater than it is later on."
Avrum Spira, MD, MSc
Summary by the AACR:
Lung cancer remains the leading cause of cancer-related death. The chances of lung cancer being cured are much higher when the cancer is caught early. Unfortunately, although lung cancer screening can be done through CT scans, it is still not certain who should be screened. In addition, developing an easier screening method, such as a blood test, can increase the likelihood that people would get themselves screened.
The Dream Team co-funded by SU2C, LUNGevity Foundation, and the American Lung Association is working to develop methods to reliably detect lung cancer at its earliest stages. In their recent publication in the journal
Nature Communications, they shared the results of their studies on bronchial biopsies and brushings.
Using bronchoscopes to obtain samples, the researchers studied premalignant lesions (PMLs) in the bronchial passages of patients who were smokers undergoing screening for lung cancer. The lesions were divided into four categories according to their genetic makeup. They focused on a subtype they called "Proliferative," which has genetic characteristics that indicate that the cells are actively dividing (as has been commonly observed in cancerous cells).
Among the "proliferative" samples, they compared those which developed into cancer and those which did not. They found indications that the immune system was more active in precancerous lesions that regressed than in lesions that eventually progressed to cancer. This suggests that lung cancer may be prevented by appropriately mobilizing the immune system at a time when precancerous lesions are detected, especially if the lesions have the genetic characteristics of the "proliferative" subtype. In addition, individuals with lesions of this subtype may greatly benefit from more frequent lung cancer screening. The team has shown that they can look for these characteristics not only in lung tissue biopsies from bronchoscopies but also possibly from less invasive sampling by using bronchial brushing.
New Factor in Pancreatic Cancer
Title: "Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring"
SU2C Authors: Daniel Von Hoff, MD; Ronald M. Evans, PhD; Geoffrey M. Wahl, PhD; Andrew M. Lowy, MD, PhD; Tannishtha Reya, PhD; Michael Downes, PhD; Tony Hunter, PhD
Grants: SU2C Pancreatic Cancer Dream Team; SU2C-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team
Published: Nature, April 17, 2019
SU2C-supported researchers studying pancreatic cancer have discovered that a protein called leukemia inhibitory factor (LIF) plays a key role in the initiation and growth of pancreatic tumors. The finding could lead to therapies targeted at LIF which, if successful, could stop or slow down growth of the cancer.
"Pancreatic cancer is a very tough problem, partly because of the dense tissue surrounding the tumor. By uncovering the previously under-appreciated role of LIF in tumor growth, we've contributed significantly to the search for new therapies for this terrible disease."
Daniel D. Von Hoff, MD
Summary by the AACR:
Pancreatic cancer has been particularly resistant to drugs, partly because the tumor is surrounded by a dense wound-like tissue called stroma. This stroma is produced by activated pancreatic stellate cells (PSCs). The activity of PSCs and pancreatic cancer cells (PCCs), and the communication between these cell types, influence pancreatic cancer progression and metastasis. The research group led by Tony Hunter, PhD, sought to understand the interaction between PSCs and PCCs, and consequently, identify new therapeutic strategies for this aggressive cancer. They shared their findings in the premier journal
Cells communicate with each other by secreting proteins that are recognized by other cells. The research group analyzed the proteins secreted by PSCs as well as the changes that resulted within the PCCs. They identified a protein called leukemia inhibitory factor (LIF), which has been previously been implicated in cancer development, due in part to its role in this intercellular communication. The researchers measured LIF levels in human pancreatic cancer tissues and observed that levels were elevated in all 77 PDAC cases that they tested. Furthermore, they observed that changes in LIF levels in the blood were correlated with how well patients responded to treatment.
Using a mouse model of pancreatic cancer, the team tested the effectiveness of an antibody that can block LIF activity. Combining the antibody with the chemotherapeutic drug gemcitabine significantly prolonged the survival of the mice. In addition, the combination was more effective in reducing tumor growth than gemcitabine alone.
The team's work indicates that LIF may not only be a biomarker of response of patients to other treatments, but also a therapeutic target by itself. The research is being carried forward by a Phase I clinical trial of an anti-LIF antibody (NCT03490669).
Key Genes in Glioblastoma Identified
Title: "Genome-wide CRISPR-Cas9 screens expose genetic vulnerabilities and mechanisms of temozolomide sensitivity in glioblastoma stem cells"
SU2C Authors: Graham MacLeod, PhD; Fiona J. Coutinho, PhD; Samuel Weiss, PhD; Peter B. Dirks, MD, PhD; Stephane Angers, PhD.
Grant: SU2C Canada Cancer Stem Cell Dream Team
Published: Cell Reports, April 16, 2019
SU2C Canada-supported scientists used the CRISPR-Cas9 tool to determine which genes in glioblastoma stem cells were required for the cells to proliferate and promote resistance to therapy.
"We think that, in one big experiment, we have uncovered many new targets for glioblastoma, some of which were surprising. These glioblastoma stem cells are also resistant to treatment, which is one reason that these tumors are so hard to cure. We need new ways to disrupt these cells specifically if we are going to give people a better chance of survival."
Peter B. Dirks, MD, PhD
Summary by the AACR:
Glioblastoma (GBM), a type of brain cancer remains largely incurable and very little progress has been made in identifying effective therapies for this disease. These tumours contain subpopulations of cells called GBM stem cells (GSCs), that drives growth and promotes resistance to therapy.
Members of the SU2C Canada Cancer Stem Cell Dream have used the gene editing tool called CRISPR-Cas9 in 10 patient-derived GSC cultures to perform a "cell fitness screen" to determine which genes in the GSCs were essential for growth and tumor progression. Multiple genes were identified as essential for tumor persistence in seven of the 10 GSC cultures tested, providing a list of potential drug targets for future therapeutic interventions.
One of the actionable drug targets is
DOT1L. The team demonstrated the effectiveness of EPZ5676, a drug currently used to treat leukemia, to inhibit the DOT1L gene product in GSCs and animal models. The researchers also performed additional screens using a chemotherapeutic drug called temozolomide -- a standard-of-care agent used to treat certain brain cancers -- to identify the genes' underlying drug sensitivity and resistance. They found that most of the genes they identified are involved in numerous pathways used to repair damaged DNA. Some of these genes are potential drug targets, and this paves the way for developing strategies for combinatorial therapy.
New Approach in Lung Cancer Treatment
Title: "Pulsatile MEK inhibition improves anti-tumor immunity and T cell function in murine
KRAS mutant lung cancer"
Published: Cell Reports, April 16, 2019
SU2C Authors: Taha Merghoub, PhD; Kwok-Kin Wong, PhD; Jedd D. Wolchok, MD, PhD
Grant: SU2C-American Cancer Society Lung Cancer Dream Team
In mouse models of lung cancer bearing the
KRAS mutation, phased administration of drugs called MEK inhibitors, plus immunotherapy, was more effective than continuous administration and may open a new path of combination treatment in humans.
"New treatments for lung cancer are urgently needed. We believe we have found a way of opening a window in which immunotherapy can be more effective in certain types of lung cancer."
Jedd D. Wolchok, MD, PhD
Summary by the AACR:
Twenty to 30 percent of patients with lung cancer have mutations in their
KRAS gene. However, no therapies have been approved by the US FDA to specifically treat patients with this mutation. Drugs called MEK inhibitors are being studied for this purpose, but resistance often develops. The SU2C-American Cancer Society Lung Cancer Dream Team aims to develop therapies for these patients. They have published promising results in the journal
Cell Reports on a treatment strategy that may be effective.
The team found that MEK inhibitors, when given to mice with
KRAS mutant lung cancer on a phased, or "pulsatile," schedule (e.g., one week on and one week off), and used in combination with immunotherapy drugs, resulted in prolonged survival of the mice.
"In this study, we show that the pulsatile schedule alters the tumor microenvironment favorably by activating T cells and providing advantageous anti-tumor effect in KRAS driven lung cancer models," the team wrote.
The team's work shows that treatments can be improved not only by discovering new drugs but also by optimizing the timing that the drugs are administered to patients. The team also demonstrated how a deeper understanding of the effects of targeted drugs can lead to rational drug combination approaches. The research is being carried forward by a phase I clinical trial where the team is comparing two different treatment regimen sequences of the MEK inhibitor trametinib and the immune checkpoint antibody anti-PD-1 (NCT03299088).
Finding New Targets in Cancer
Title: "Prioritisation of cancer therapeutic targets using CRISPR-Cas9 screens"
SU2C Author: Mathew J. Garnett, PhD
Grants: SU2C–Dutch Cancer Society Tumor Organoids Dream Team
Published: Nature, April 10, 2019
SU2C-supported scientists have used the powerful new genome editing technology CRISPR-Cas9 to identify genes that are important to the growth and function of cells in several different tumor types. These genes can be used as targets in the development of drugs, hopefully identifying new targeted therapies for different types of cancer.
"Patients will benefit from greater availability of therapies that are targeted to their specific cancers. Our research is dedicated to finding the vulnerabilities in tumor genomes that can be targeted with new drugs. We hope our research, by identifying the most promising targets, will help bring forth new drugs to fight cancer."
Mathew J. Garnett, PhD
Summary by the AACR:
Targeted cancer therapies are continuously being developed to more effectively treat patients based on patients' genetic characteristics. However, there still remains a lot to learn on the characteristics of tumors that can be targeted by drugs. In a paper published by the research group jointly funded by SU2C and the Dutch Cancer Society, scientists used an emerging genetic technique, called CRISPR-Cas9, to identify new target proteins in cancer cells. They shared their findings in
Nature, the world's most-cited journal of interdisciplinary science.
CRISPR-Cas9 can be used to effectively shut down the function of a specific protein to identify which proteins are most needed by cells. The research group knocked down 18,009 different genes in more than 300 cancer cell lines, representing 30 different types of cancers. The cancer types that they tested included the most common (lung, colon, and breast), and those that have caused the highest number of deaths (lung and pancreatic).
The team developed a statistical method to distinguish which genes affected most of the cancer cell lines. They surmised that targeting these genes, although may seem advantageous, may also affect normal cells and therefore, cause toxicity in patients. Instead of focusing on these genes, they focused on prioritizing those which were important to the growth of specific subsets of cancer cell lines that share similar genetic characteristics or tissues-of-origin. They identified 628 priority targets, 120 of which are promising to pursue for drug development.
More than 20 cancer types have a highly unstable genome because of an impairment in their DNA repair capacity. These are referred to as cancers with microsatellite instability (or MSI cancers). This characteristic can be seen in a subset of colon, ovarian, endometrial and gastric cancers. The research group identified a protein called WRN helicase as a promising target in MSI cancers. WRN helicase is what is referred to as a synthetic lethal target because blocking WRN function exacerbates the DNA repair deficiency of MSI cancers. The group suggests exploring the use of WRN antagonists in combination with approved immune checkpoint antibodies for MSI cancers. Dr. Garnett's work demonstrates how using the more novel genetic tool called CRISPR-Cas9, along with statistical and mathematical methods, can yield to new drug targets and therapeutic strategies.
New Drug Target in Pancreatic Cancer
Title: "A multiscale map of the stem cell state in pancreatic adenocarcinoma"
SU2C Authors: Daniel D. Von Hoff, MD; Haiyong Han, PhD; Andrew M. Lowy, MD; Tannishtha Reya, PhD
Grants: Pancreatic Cancer Collective New Therapies Challenge; SU2C–Cancer Research UK–Lustgarten Foundation Pancreatic Cancer Dream Team
Published: Cell, April 4, 2019
Promising results from SU2C-funded researchers point to a new drug target in pancreatic cancer stem cells resistant to chemotherapy: the receptor protein ROR gamma. With ROR gamma pathway blockers already being tested in Phase II trials for autoimmune diseases, these results point to the possibility of repurposing these agents to treat pancreatic cancer.
"We must find a better way to treat pancreatic cancer. Our work in mapping molecular dependencies in chemotherapy-resistant pancreatic cancer stem cells points to a possible new path: drugs already being evaluated in autoimmune disease. They may also be effective against pancreatic cancer."
Tannishtha Reya, PhD
Summary by the AACR:
Chemotherapy remains the standard of care for pancreatic cancer. Unfortunately, only 30 percent of patients respond, and the disease soon progresses in most of them. The rapid disease recurrence after chemotherapy indicates that there are drug-resistant cells that survive chemotherapy and grow back rapidly; these are known as stem cells. In a paper published by the research group jointly funded by SU2C-Cancer Research UK and Lustgarten Foundation, scientists identified a therapeutic target in these drug-resistant cells. They shared their findings in the journal
In an effort to develop new treatment strategies to target these drug-resistant cells, Tannishtha Reya, PhD, and the team identified the proteins that impart unique characteristics to these pancreatic cancer stem cells. They saw that one of these proteins, ROR gamma, is already being targeted in the treatment of autoimmune diseases in phase II clinical trials. Thus, work already being done with ROR gamma inhibitors in autoimmune diseases may help to hasten their use in the clinic if they are found to be effective against pancreatic cancer also.
The group also confirmed that combining a ROR gamma pathway blocker with the chemotherapeutic drug gemcitabine was more effective in stopping pancreatic growth in the laboratory than gemcitabine alone. They looked at samples from pancreatic cancer patients and observed that the levels of ROR gamma correlated with aggressiveness of the cancer. These results strengthen the case that ROR gamma plays an important role in pancreatic cancer progression, and that blocking ROR gamma is a promising treatment strategy for this deadly disease.
This research falls within the portfolio of the Pancreatic Cancer Collective, the strategic partnership of Lustgarten Foundation and SU2C.
Two-Drug Combination in Ovarian Cancer
Title: "Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial"
SU2C Authors: Alan D. D'Andrea, MD, team leader; Elizabeth M. Swisher, MD, co-leader; and others.
Grant: SU2C–Ovarian Cancer Research Fund Alliance–National Ovarian Cancer Coalition Ovarian Cancer Dream Team
Published: Lancet Oncology, March 14, 2019
Work by SU2C-supported researchers found encouraging indications for using drugs called PARP inhibitors to fight ovarian cancer in a set of patients in whom they would not usually be effective because their tumors feature a DNA repair pathway that is functioning normally. The team observed synergy with another drug that, among other things, inhibits the repair pathway and thereby makes cells vulnerable to PARP inhibitors, thus halting or slowing down the cancer.
Summary by the AACR:
The homologous recombination repair (HRR) pathway is one of the major pathways involved in repairing damaged DNA in cells. BRCA1 and BRCA2 proteins are involved in the repair of damaged DNA and play an important role in the HRR pathway. PARP inhibitors (PARPi) are drugs that are FDA-approved in patients with HRR deficiencies, such as those having BRCA1/2 mutations. Unfortunately, patients often have an intact HRR pathway or they acquire HRR proficiency, leading to resistance to PARPi. Hence, researchers have investigated the idea of combining PARPi with drugs that can inhibit the HRR pathway. One such class of drugs are PI3K inhibitors that not only inhibit the HRR pathway but have also shown synergy with PARPi in pre-clinical studies.
Members of the SU2C–Ovarian Cancer Research Fund Alliance–National Ovarian Cancer Coalition Ovarian Cancer Dream Team initiated a phase 1b clinical trial (NCT01623349) of olaparib, a PARPi, combined with either buparlisib (pan-PI3K inhibitor) or alpelisib (PI3Kα inhibitor) in patients with ovarian cancer and patients with breast cancer. Initial studies with buparlisib showed no advantage in combining it with olaparib and resulted in toxic side effects in the central nervous system. To overcome this, in this study the team evaluated the combination of alpelisib with olaparib, with the aim to assess the safety and find a recommended phase 2 dose of the drug combination. The team enrolled 34 patients (30 with epithelial ovarian cancer and four with breast cancer) on the trial with this combination.
The combination did not yield any unexpected toxic side effects. Data from the trial shows that 36 percent of patients had a partial response, 50 percent had stable disease, and 3 percent progressed. They did not observe any benefit of this combination in platinum-resistant patients with BRCA mutations. However, they observed an overall response rate of 33.3 percent with this combination in platinum-resistant patients with no BRCA mutations, compared to the reported 5 percent overall response with the use of PARPi only in this population. Prior studies have also not reported much success in using PI3K inhibitors alone in epithelial ovarian cancer. Overall, these findings provide evidence of synergy in the combination of a PI3K inhibitor and PARPi in HRR-proficient ovarian cancers.
The team published its findings in the prestigious journal
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
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. 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."
Gregory L. Beatty, MD, PhD
Summary by the 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
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. 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."
Martin McMahon, PhD
Summary by the AACR:
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"
SU2C Author: Kurt Schalper, MD, PhD
Title: "Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma"
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 the 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
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
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 the 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
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 the 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 the 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.