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FINDING CURES TOGETHER<sup>SM</sup>

Scientific Highlights 

Special Report on AACR Pancreatic Cancer Conference

By Christina Leah Kline, PhD
Senior Scientific Program Administrator
American Association for Cancer Research

With a five-year survival rate of only 8 percent, pancreatic cancer is a major challenge to the research community. Finding new ways to detect and treat cancer of the pancreas is a significant focus of Stand Up To Cancer, leading to an important new partnership with the Lustgarten Foundation for Pancreatic Cancer Research (LF). Exciting new insights into pancreatic cancer, and the challenges that remain, were discussed in depth at a recent special conference organized by the American Association for Cancer Research (AACR), Scientific Partner of SU2C, a meeting for which the Lustgarten Foundation was a lead supporter. Many of the presentations involved work supported by SU2C and/or Lustgarten.

"The meeting covered a multitude of pertinent topics, including the use of imaging and blood-based early detection to diagnose pancreatic cancer at the earliest stages possible, preferably in the occult period before it becomes symptomatic," said Anirban Maitra, MBBS, scientific director of the Sheikh Ahmed Pancreatic Cancer Research Center at The University of Texas MD Anderson Cancer Center and leader of the SU2C-LF Pancreatic Cancer Interception Dream Team. "This is crucial if we want to intercept the progression of pancreatic cancer to a metastatic stage that has dismal patient outcomes."

Held in Boston in late September, AACR's Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care brought together top researchers of the field, along with promising young investigators, many of whom are associated with SU2C- and Lustgarten-funded research. Here are some of the highlights of the conference: 

  • David A. Tuveson, MD, PhD, Lustgarten's chief scientific officer and SU2C Scientific Advisory Committee member, shared his research group's foray into characterizing fibroblasts, one of the cell types that are found in the pancreatic cancer stroma -- the material surrounding the cancer.  The stroma is very complex, and this contributes to the difficulty in treating the cancer. By understanding the cells that can be found in the stroma, like fibroblasts, new strategies for treating pancreatic cancer can be devised.

  • Vinod P. Balachandran, MD, a surgeon at Memorial Sloan Kettering Cancer Center in New York, and leader of the SU2C-LF-Society for Immunotherapy of Cancer (SITC) Pancreatic Cancer Convergence Research Team, spoke on his work with long-term survivors of pancreatic cancer. Because they are so rare, studying the immune system on these patients can provide insights on how to harness the body's defense system for therapy, he said.  His talk spurs new questions on the rate of metastasis in long-term survivors, and how chemotherapy affects high and low-quality neoantigens.

  • Ronald M. Evans, PhD, director of the Gene Expression Laboratory at the Salk Institute for Biological Studies, and co-leader of the SU2C-Cancer Research UK-LF Pancreatic Cancer Dream Team, reported on the team's ongoing work on understanding epigenetic regulation of pancreatic cancer genomic networks. His team has shown that a vitamin D receptor agonist like paricalcitol can oppose activated stem cell gene expression networks, he said. He also shared their findings on how entinostat, a drug that can inhibit an enzyme involved in DNA packaging, can inhibit cancer cell survival. The team's preclinical insights are now being translated to the clinic, with preliminary approval of a clinical trial on the combination of the epigenetic drug entinostat with FOLFOX, and planned and ongoing clinical trials on the addition of paricalcitol to treatment regimens.

  • Joseph M. Herman, MD, a professor of radiation oncology at MD Anderson and a principal investigator on the SU2C-LF Pancreatic Cancer Interception Research Team, spoke on the merits of stereotactic body radiotherapy (SBRT). A patient can receive SBRT during outpatient visits for five consecutive days, in stark contrast to the conventional six-week course of radiation. In addition, SBRT is less immunosuppressive than chemoradiation, he said.  This new radiation therapy strategy will be studied by the research team, along with the anti-hypertensive medication losartan, which has been shown in laboratory experiments to be able to change the tumor microenvironment – potentially making it easier for cancer-killing T cells to reach the tumor.

  • Marcia Irene F. Canto, MD, from Johns Hopkins University in Baltimore, an investigator on the Interception Dream Team, said data show that surveillance of people at high risk of pancreatic cancer can potentially improve survival of those who develop disease. A study showed that high-risk individuals whose pancreatic cancers were detected during scheduled screenings survived longer than high-risk individuals whose cancers were detected outside surveillance, she said. These results support ongoing efforts to encourage high-risk individuals to undergo regular screening to detect their cancer early.

  • Screening was also addressed by Sapna Syngal, MD, MPH, director of research at the Center for Cancer Genetics and Prevention at Dana-Farber Cancer Institute, also a principal on the Interception Dream Team. Previously, pancreatic cancer patients were urged to communicate to their loved ones that they, too, should be screened. But this approach was not effective, she said, giving impetus to one of the clinical trials that will be conducted by the Interception Dream Team. The clinical trial is called GENERATE – GENetic Education Risk Assessment and TEsting. The goal of the study is to increase uptake of genetic testing. 

  • She also described how the Interception Dream Team is addressing the goal of developing early screening methodologies for pancreatic cancer from all angles – encouraging people to undergo genetic screening, developing imaging and blood-based methods to detect cancer early, and developing vaccines for high-risk individuals to prevent cancer development. She underscored the role of the team's patient advocates who regularly guide the team to more effective communication strategies with patients. 

  • Elliott K. Fishman, MD, director of diagnostic imaging and body CT (computed tomography) at Hopkins, spoke of his work on 3D imaging of the pancreas with Michael G. Goggins, MD, professor of oncology at Hopkins, and co-leader of the Interception Dream Team. He indicated that the imaging will help detect the development of cancer based on the structural changes in the pancreas. 

  • Ongoing efforts to develop blood-based screening tests for early detection were shared by another Interception Dream Team principal investigator, Nickolas Papadopoulos, PhD, professor of oncology at Hopkins. In a blood-based test, the researchers seek to integrate information from promising biomarkers (circulating DNA, proteins, metabolites) and develop a blood test for diagnosing pre-symptomatic cancer. 

The conference was capped by a panel discussion on clinical trials. What was clear was a resounding call for collaboration between basic and translational scientists, and collaboration between institutions. Invigorated by the urgency of the problem, and the promise of progress, with the support of funding partners, attendees can look forward to reconvening in the next Special Conference.

© American Association for Cancer Research October 2018

Genomic correlates identified for response or resistance to immunotherapy 

Immunotherapy has been effective in some patients with different cancer types. However, at this point, doctors cannot predict which patients will respond to immunotherapy. Some scientists have seen that patients with a higher number of mutations are more responsive to immunotherapy. However, the connection between the number of mutations and responsiveness to immunotherapy is not well established, limiting the utility of using the number of mutations to predict patients' response to immunotherapy.

Members of the SU2C-American Cancer Society Dream Team, led by Eliezer Van Allen, MD, of DFCI and the Broad Institute, worked on identifying other predictors of response to immunotherapy. They published their work in Nature Genetics. They analyzed 249 patient samples representing six different cancer types, including lung cancer. They found that not only do the number of mutations matter, but also the identity of the genes that are mutated or lost can influence whether a patient will respond or will be resistant to immunotherapy. Ultimately, these findings could help improve patient care by reliably and robustly identifying biomarkers of response and intrinsic resistance to immune checkpoint blockade.

SU2C’s prostate cancer teams identify roots of resistance, open door to more effective treatments

Stand Up To Cancer’s two teams on prostate cancer have reported findings that identify a way in which the tumors become resistant to treatment, and also open the door to more effective personalized treatment of advanced disease. 

Cancer localized to the prostate is generally a manageable disease with good life expectancy: 98 percent of men with localized disease survive five years or more from diagnosis. But when the disease spreads beyond the prostate, five-year survival plunges to only 30 percent, according to the National Cancer Institute. Two SU2C Dream Teams have been investigating the origin of resistance and new ways to treat metastatic disease. 

Surprising finding on prostate cancer subtype

Eric J. Small, MD, The SU2C-Prostate Cancer Foundation Dream Team on Targeting Adaptive Pathways in Metastatic Castration-Resistant Prostate Cancer, based at University of California San Francisco and led by Eric J. Small, MD, working with other researchers, delved into the clinical and genomic features of a form of prostate cancer known as treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC).  

It had been thought that this variant accounted for only about 1 percent of all prostate cancers. To the research team’s surprise, about 17 percent of the 160 tumors they studied were classified as t-SCNC.  The finding is important because men with t-SCNC tend to have a shorter survival time than men with other forms of metastatic prostate cancer. Unraveling its genetic makeup is critical to determining how indolent prostate cancer becomes resistant to treatment and becomes metastatic. 

"An understanding of the biology of this important mechanism of resistance is essential to our developing novel therapeutics designed to prevent the development of this lethal prostate cancer subtype or, once developed, to effectively treat it," said Dr. Small, senior author of the paper and professor of medicine and chief of the Division of Hematology and Oncology at UCSF. Small is also deputy director of the UCSF Helen Diller Family Comprehensive Cancer Center. The team’s findings were published in the Journal of Clinical Oncology. 

Teams work together on publication in Cell

Arul Chinnaiyan, MD, PhDSmall teamed up with Arul Chinnaiyan, MD, PhD, professor of pathology and urology at the University of Michigan Medical School and leader of the SU2C-Prostate Cancer Foundation Dream Team on Precision Therapy of Advanced Prostate Cancer based at Michigan, and others, for a second publication, this one in Cell, a top-rated journal in the life sciences. 

The team analyzed biopsy samples from more than 100 men and found structural alterations in the prostate cancer genomes that were propelling the metastatic form of the disease. There were alterations that were associated with the loss of function in genes that normally repair damaged DNA, according to the paper. Other structural changes result in the activation of oncogenes that drive cancer, or inactivation of genes that suppress the growth of tumors. 

“The impact of the observations from this project reflect a remarkable collaborative effort across the multiple institutions of the “West Coast” Prostate Cancer Dream Team, and beyond,” said Small. “These whole-genome sequencing data are particularly impactful in that they are derived from biopsies of metastases in men with castration-resistant prostate cancer.” 

Impact of mutations assessed
Aside from mutations, the DNA sequence can be changed when certain segments are removed or duplicated, or when a segment of DNA is inserted into a new position. The team found that the genes that are most disrupted by these changes in DNA arrangements are the genes that drive the development of prostate cancer, such as the genes coding for the androgen receptor, and the Myc and PTEN protein. In 70 percent of the samples, there were multiple copies of the androgen receptor gene. This can in part explain resistance to hormone therapy. In addition, the team also observed gene fusions that may activate the oncogenes AXL and BRAF. The good news is that there are drugs that are being developed to treat cancers that have these characteristics. 

Abstracts of the papers are available:
Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study
Journal of Clinical Oncology July 9, 2018, https://doi.org/10.1200/JCO.2017.77.6880

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

SU2C scientists zero in on source of sensitivity to anti-tumor drugs

SU2C scientists have used a new genetic screening method to zero in on locations in the human genome that could lead to more effective targeted use of powerful drugs to treat prostate cancer and possibly chronic lymphocytic leukemia, according to a paper published in Nature, the world's top-rated journal of multidisciplinary science.

Drugs known as PARP inhibitors wreak havoc on the cell division process that causes cancer, eventually bringing about the death of the cancer cells. Olaparib, a drug already widely used against ovarian cancer, is a PARP inhibitor. 

Johann de BonoA team including Johann de Bono, MD, PhD, of the Institute for Cancer Research in London, a principal investigator on an SU2C-Prostate Cancer Foundation Dream Team, used a method called CRISPR (clustered regularly interspersed palindromic repeats) to screen for genes in human cancer cell lines that affect sensitivity to olaparib. They were looking for genomic regions that hosted large amounts of PARP, an enzyme involved in cell reproduction and the target of olaparib and other PARP inhibitors.

The team confirmed previously reported findings that when genes involved in repairing  DNA are disrupted, the cells become more sensitive to olaparib. They also observed that cells become more vulnerable to olaparib when other genes – specifically the RNase H2 complex – are inhibited. One of the functions of RNase H2 is to repair DNA in situations when the wrong building blocks are incorporated during DNA synthesis, so inhibiting this process can lead to death of cancerous cells. The enzymes encoded by these genes tend to cluster in damaged portions of DNA.

These regions are "a hitherto unappreciated source of PARP-trapping DNA lesions," the scientists wrote. With other experiments, they also found that loss of the RNase H2 renders the cancer cells more sensitive to talazoparib, another PARP inhibitor. Out of 226 samples from patients with metastatic castration-resistant prostate cancer, they found that 34 percent of the tumors had lost their RNase H2 genes. This loss in RNase H2 may explain in part the beneficial effect of PARP inhibitors in some patients.

These results provide more information on genetic characteristics that can be used to predict response of metastatic prostate cancer patients to PARP inhibitors. Loss of the of RNase H2 genes was also found in 43 percent of chronic lymphocytic leukemia (CLL) samples, suggesting the potential utility of PARP inhibitors for the treatment of CLL.

The abstract of the paper, "CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions," can be found at https://doi.org/10.1038/s41586-018-0291-z

SU2C support: The research was supported in part by the SU2C-Prostate Cancer Foundation Prostate Cancer Dream Team: Precision Therapy of Advanced Prostate Cancer.

An SU2C investigator is published in world’s top journal

Matthew Vander Heiden, MD, PhD, of the Massachusetts Institute of Technology, received an Innovative Research Grant (IRG) from SU2C in 2016 to study cancer metabolism and has just published papers in the prestigious journals Nature and Nature Cell Biology that highlight his work. 

Matthew Vander Heiden, MD, PhDVander Heiden’s research revolves around the fact that cancer cells, like normal cells, require nutrients to survive. The way cancer cells use nutrients (i.e., cancer metabolism) is different from that of normal cells. A better understanding of this difference may reveal ways to exploit changes in cancer metabolism and identify targets for new drugs and improved treatment. 

His recent publications explore two issues related to tumor metabolism: the loss of muscle tissues in pancreatic cancer, a metabolic syndrome that lowers quality of life and which may decrease patient survival; and the role of an amino acid called aspartate in promoting tumor growth. 

In an article in Nature, the world’s highest-rated journal of multidisciplinary science, the research team led by Vander Heiden focused on understanding the reason behind the loss of fat and muscle tissue in patients with pancreatic cancer. Studying mouse models for pancreatic cancer, they found that this tissue wasting is a result of decreased effectiveness of the pancreas as the cancer progresses. 

Administering some of the important pancreatic enzymes staved off fatty tissue loss in the mouse model, the researchers found. Additional studies are needed, however, to further understand how to treat pancreatic cancer patients who are experiencing significant tissue loss. 

In their publication in Nature Cell Biology, Vander Heiden’s team homed in on the importance of aspartate to cancer metabolism. They saw that when cancer cells have more aspartate, they can grow faster. This underscores the importance of limiting aspartate levels that are available to cancer cells. One way to do is to block mitochondrial respiration, for example by using the antidiabetes drug metformin. An important caveat, however, is that not all cancers are equally dependent on aspartate. For instance, increasing intracellular aspartate levels of the pancreatic cancer cell line AsPC-1 did not push the cancer to grow faster. Thus, blocking aspartate production may be effective against some, but not all cancer types. 

The abstract of "Altered exocrine function can drive adipose wasting in early pancreatic cancer" in Nature is available at http://dx.doi.org/10.1038/s41586-018-0235-7.

The abstract of "Aspartate is an endogenous metabolic limitation for tumour growth" in Nature Cell Biology at http://dx.doi.org/10.1038/s41556-018-0125-0.

(June 28, 2018)

SU2C Innovative Research Grant recipient explores strategy against AML

A 2017 recipient of SU2C’s Innovative Research Grants (IRG) aimed at up-and-coming young investigators, Daniel Bachovchin, PhD, of Memorial Sloan-Kettering Cancer Center, has just published a study in the prestigious journal Nature Medicine suggesting a new approach to killing cancer cells in acute myeloid leukemia.

Daniel BachovchinBachovchin’s IRG project revolves around an intriguing but poorly understood small molecule drug called Val-boroPro or talabostat, which has been shown to activate the body’s immune system to attack cancer. Val-boroPro blocks the action of two proteins called Dpp8 and Dpp9 and consequently causes cancer cells to die.


In the Nature Medicine paper, Bachovchin and his co-authors explored the question of whether inhibiting Dpp8 and Dpp9 can be a treatment strategy for treating acute myeloid leukemia (AML). They found that Val-boroPro was effective in killing AML cells in the laboratory. In addition, they looked for potential predictors of response. They found that when AML cells have higher levels of two proteins called CARD8 and pro-caspase-1, the cells were more likely to be sensitive to Val-boroPro. CARD8 and pro-caspase-1 play important roles in the cell death process called pyroptosis.

“The small molecule drug Val-boroPro has long been known to stimulate anticancer immune responses, but how it did so remained a mystery for more than a decade,” Bachovchin explained. “Here, we show a key piece of Val-boroPro’s mechanism, specifically that it activates an inflammatory form of cell death mediated by a protein called CARD8. Interestingly, this cell death only happens in certain cells in the immune system, including cancerous AML cells.”

“We further show that Val-boroPro can directly kill AML cells in animal models. We are now working to further explore both the anticancer potential of Val-boroPro as a cytotoxic agent against AML and as a cancer immunotherapy agent,” he said. 

The paper, “DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia” was published July 2. The abstract is available at: (DOI): 10.1038/s41591-018-0082-y. Enter the DOI number in your browser’s search field to get to the abstract. 

(July 2, 2018)

SU2C Scientists Work to Expand Immunology in Blood and Brain Cancers

Findings published in prestigious journal Nature Medicine

Scientists supported by Stand Up To Cancer are continuing to make strides in chimeric antigen receptor (CAR) T technology, which uses the body's own immune system to attack cancerous cells.  

The latest pieces of important research are in chronic lymphocytic leukemia (CLL), a blood cancer affecting mainly adults, and in diffuse midline gliomas (DMGs), brain tumors found in children that are usually fatal. Both pieces of work were published in the prestigious journal Nature Medicine.

In the case of CLL, scientists supported by a Phillip A. Sharp Innovation in Collaboration Award identified biomarkers that can help predict whether T-cell therapy will work in specific patients; if not, patients could be steered to treatments that may be more successful for them. And in DMGs, scientists on the SU2C-St. Baldrick's Foundation Pediatric Cancer Dream Team showed that CAR-T cells can be engineered to attack molecules found in abundance on the surfaces of gliomas.

The researchers addressed some of the questions around CAR-T therapy, in which scientists modify a patient's own immune cells in the laboratory, then infuse them back into the patient to attack and kill the cancer cells. CAR-T therapy has been most successful so far in acute lymphoblastic leukemia (ALL) but not so successful in CLL or in solid tumors. 

(May 2018)

Leukemia

Carl H. June, MDThe work in CLL was performed by a team that included Carl H. June, MD, the Richard W. Vague professor in immunotherapy at the University of Pennsylvania's Perelman School of Medicine. Along with Shelley L. Berger, PhD, the Daniel S. Och university professor at Perelman, June received an SU2C Phillip A. Sharp Innovation in Collaboration Award in 2016. These are awards given to encourage collaboration among SU2C research units; they are named for Phillip A. Sharp, PhD, the chair of the SU2C Scientific Advisory Committee.

Based on samples from 41 patients, the researchers observed that the genes expressed by T cells from patients who responded to the therapy were different from T cells from those who didn't respond. Specifically, the non-responders had more expression of genes that were associated with exhaustion and death of the T cells. This means that it may be possible to predict which patient can respond well to CAR-T therapy by analyzing a patient's T cells for the expression of certain genes. This could keep the patients from being treated with a therapy that may be less likely to be effective, and saves the time and cost of modifying the T cells in the laboratory if they will not be effective anyway. The study also indicates the potential use of more effective, optimized CAR-T cells, and shows that overall biomarker-driven approaches may be applicable to other cancers.

(May 2018)

Gliomas

Another challenge in CAR-T cell therapy is applying it to solid tumors, as opposed to blood cancers.  Researchers with the SU2C-St. Baldrick's Foundation Pediatric Cancer Dream Team have, for the first time, identified a target in a brain tumor known as diffuse midline glioma (DMG) with mutation in the histone H3 (K27M mutation). These tumors occur in children, and have a very poor prognosis.

Crystal L. Mackall, MDCrystal L. Mackall, MD, co-leader of the Dream Team and director of the Stanford Center for Cancer Cell Therapy at Stanford University, senior author of the paper, wrote that the target is a protein called GD2 that is overexpressed in the tumors. T cells can be modified to home in on the tumors and wipe them out.


The team's experiments were carried out in mice with implanted tumors. The favorable results could pave the way to human clinical trials.

"If the results in mouse models are predictive of results in humans, this immunotherapeutic strategy could be transformative for the outcomes of children with H3-K27M-mutant DMGs," she wrote.

The Dream Team has been in operation since 2013 and has been associated with some of the biggest breakthroughs in CAR-T cell immunology. SU2C recently announced that the team will continue its work under the SU2C umbrella but with funding from St. Baldrick's Foundation exclusively.

(May 2018)

Research

Abstracts of these papers are on the Nature Medicine website. Use the "doi" number to search:
Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia
by Joseph A. Fraietta, Carl H. June, J. Joseph Melenhorst, et al.,
Nature Medicine (2018) doi:10.1038/s41591-018-0010-1

Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas
Christopher W. Mount, Michelle Monje, and Crystal L. Mackall
Nature Medicine (2018), doi:10.1038/s41591-018-0006-x
(May 2018)

© AACR May 2018