Christin Melton, ELS, CMPP

A research team led by investigators at the University of Texas Southwestern Medical Center in Dallas has published a study in

identifying several new genetic mutations in pancreatic ductal adenocarcinoma (PDA).

Pancreatic ductal adenocarcinoma is the predominate subtype of pancreatic cancer, accounting for more than 90% of cases.

Historically, the complexity of PDA has hindered efforts to unravel its etiology, assess prognosis for individual patients, and develop effective targeted therapies to improve the dismal outcomes associated with this disease. &ldquo;We identified a wealth of genetic diversity, including multiple mutated genes that were previously unknown to pancreatic canceran important step in gaining a better understanding of this difficult and particularly deadly disease,&rdquo; said lead author Agnieszka Witkiewicz, MD, associate professor of pathology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern, in a press release.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in men and women.

Approximately 49,000 cases of pancreatic cancer will be diagnosed in 2015. The lack of a reliable screening method to detect pancreatic cancer means more than half of cases (53%) will be diagnosed after the cancer has metastasized. As a result, only 20% of patients are candidates for surgical resection; standard treatment for unresectable disease is systemic chemotherapy. After surgery or chemotherapy, patients invariably relapse. Patients with pancreatic cancer have a poor prognosiseven those whose tumor was still localized at diagnosis. Overall, only 28% of patients survive 1 year after diagnosis, and only 7% survive 5 years.

Although targeted treatments have been approved for pancreatic neuroendocrine tumors, which make up about 5% of pancreatic cancer diagnoses, no targeted therapies are available for PDA.

The main obstacle to obtaining genetic information about PDA is the fact that tissue specimens from PDA tumors typically contain a mix of tumor cells and normal cells, which makes it difficult for scientists to identify genetic defects amenable to treatment. To improve the yield of tumor cells, the research team used needle dissection on PDA specimens taken from 109 patients who underwent surgical resection. Then they performed whole-exome sequencing, which revealed a genetic diversity similar to that observed in other solid tumors.

The researchers confirmed the existence of some previously known oncogenic drivers and identified several new ones. Some of the newly discovered genetic mutations, such as

, occurred relatively infrequently; whereas others, like

, and mutations targeting the SWI/SNF pathway, were more common. Therapies targeting some of the genetic alterations the researchers found in the PDA samples are already approved or under development for other types of cancer. For example, they found

mutations in PDA wild-type KRAS tumors. A

-positive cell line of PDA they cultured proved just as susceptible to treatment with the FDA-approved BRAF inhibitor vemurafenib as a melanoma cell line used as a comparator. In addition to serving as therapeutic targets, the genetic aberrations they discovered may offer new insights on etiology and prognosis. Data associated pancreatic tumors with greater chromosomal instability with worse prognosis. Another important finding was a correlation between Myc amplification, adenosquamous histology, and poor prognosis. Smoking status proved to be a driver and prognostic factor in the PDA cases they examined. The mutational profile of smokers with PDA was similar to the mutational profile reported for other smoking-related cancers. In addition, smokers with PDA survived less than half as long as nonsmokers in the study.

&ldquo;I am considerably more optimistic of the utility of a genetically targeted therapy for pancreatic cancer today than when we began this work,&rdquo; said senior author Erik Knudsen, PhD, professor of pathology, Simmons Cancer Center, in a press release.

He added that much more research is needed, however. Witkiewicz cautioned that while the discoveries are exciting, &ldquo;Most pancreatic cancers exhibit multiple genetic alterations; therefore, it is likely that combination approaches targeting multiple pathways will be required for effective disease control.&rdquo;

Witkiewicz AK, McMillan EA, Balaji U. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets.

Researchers lead collaborative charge to uncover genetic diversity of pancreatic cancer [press release]. http://www.utsouthwestern.edu/newsroom/news-releases/year-2015/april/pancreatic-cancer-knudsen.html. Accessed April 13, 2015.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015.

Articles

A research team led by investigators at the University of Texas Southwestern Medical Center in Dallas has published a study in Nature Communications identifying several new genetic mutations in pancreatic ductal adenocarcinoma.

Whole-Genome Sequencing Identifies New Targets in Pancreatic Cancer

Immunotherapy vaccine approaches that involve harvesting a patient&rsquo;s dendritic cells and priming them to recognize a tumor-specific antigen before injecting them back into the patient to activate a T-cell response against the tumor have achieved encouraging but limited success.

For example, men with prostate cancer treated with the dendritic-based vaccine sipuleucel-T typically respond but eventually experience disease progression.

Researchers have increasingly been looking at various ways to enhance the effectiveness of immunotherapy against different types of cancer.

A US study jointly funded by the National Institute of Neurological Disorders and Stroke and the National Cancer Institute found that administering a tetanus booster shot at the site where the dendritic-based vaccine was subsequently injected improved median overall survival in 12 patients with glioblastoma.

Patients were randomly assigned to receive the tetanus booster followed by an injection of dendritic cells programmed with a cytomegalovirus antigen or to an injection of autologous nonprogrammed dendritic cells followed by an injection of the primed dendritic cells.

Investigators found a greater number of dendritic cells had migrated to the lymph nodes in patients who received the tetanus booster and the overall survival in this group was 36.6 months compared with 18.5 months for patients who did not receive the booster shot.

One woman who received the treatment is alive after 9 years. Although the findings are promising, a much larger trial is needed to confirm the results.

The focus in immunotherapy vaccine research has expanded in recent years to include the use of modified T-cells. Guenther Koehne, MD, a medical oncologist and medical director of the Memorial Sloan Kettering Cancer Center&rsquo;s (MSKCC&rsquo;s) Cytotherapy Lab, is an investigator for a phase I trial evaluating T cells modified to target Wilms tumor antigen 1 (WT

) in patients with multiple myeloma or plasma cell leukemia.

A video posted at the MSKCC website in April 2014 discusses the case of Ruth Lacey, the first patient Koehne treated with the WT

Lacey had multiple myeloma that progressed to plasma cell leukemia after chemotherapy, and she had exhausted all standard treatment options. At Koehne&rsquo;s recommendation, she underwent an allogeneic stem cell transplant. After the transplant, Lacey still had active disease. With the US Food and Drug Administration&rsquo;s (FDA&rsquo;s) consent, Koehne gave Lacey an infusion of WT

-specific T cells harvested from the T lymphocytes of Lacey&rsquo;s stem cell donor, cultivated in the laboratory, and pulsed with WT

peptides, a protein overexpressed in various cancers, including multiple myeloma. The modified T cells bound to the WT

protein as anticipated and eradicated the myeloma cells. After 2 additional WT

-specific T-cell infusions, Lacey achieved a complete remission, which she maintained for more than 2 years before her disease relapsed.

In the video, Koehne describes the new vaccine strategy as a &ldquo;game changer.&rdquo;

In Koehne&rsquo;s ongoing phase I trial, patients with multiple myeloma or plasma cell leukemia undergo an allograft transplant (human leukocyte antigenmatched or unmatched) and receive the first infusion of WT

-specific T cells 6 to 10 weeks later. If the investigator considers it safe, the patient receives 2 more infusions of the WT

-specific T cells. Koehne recently told the UK Daily Mail that 15 patients have been treated in the trial, all with a prognosis at enrollment of mere months and few treatment options.

The Daily Mail article notes that British researchers at the University College London and Royal Free Hospital are evaluating a similar immunotherapy approach in which T cells are harvested directly from patients with leukemia, exposed in the laboratory to particles carrying WT

protein DNA, and re-infused into the patient.7 The US Army Medical Research and Materiel Command, MSKCC, and MD Anderson Cancer Center are collaborating on a phase II trial to determine whether or not the WT

peptide vaccine can prevent the recurrence of mesothelioma, another cancer that expresses high levels of WT

The Seattle Cancer Care Alliance is also investigating different T-cell immunotherapy approaches in cancer and has several trials under way.

A vast amount of research is evaluating a plethora of immunotherapy approaches in oncology. Data on some of novel vaccine strategies will be presented at the 2nd Immunotherapy of Cancer Conference, being held from March 25-27, 2015, in Munich, Germany. The conference also includes a plenary session on immunotherapy vaccines.

A CME conference sponsored by Physician&rsquo;s Education Resource (PER) called Transforming Immuno-Oncology Across Solid Tumors, will take place in Chicago, IL on Friday May 29th, 2015.

Bear AS, Cruz CR, Foster AE. T cells as vehicles for cancer vaccination.

Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

National Institutes of Health. Strengthening the immune system's fight against brain cancer [press release]. http://www.nih.gov/news/health/mar2015/ninds-18.htm. Published March 18, 2015. Accessed March 24, 2015.

Mitchell DA, Batich KA, Gunn MD, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

Memorial Sloan Kettering Cancer Center. Guenther Koehne, MD, PhD biography. http://www.mskcc.org/cancer-care/doctor/guenther-koehne. Accessed March 24, 2015.

Memorial Sloan Kettering Cancer Center. Case study: WT1-specific T-cell responses in a patient with plasma cell leukemia and relapsed refractory multiple myeloma. http://www.mskcc.org/videos/case-study-wt1-specific-t-cell-responses-patient-plasma-cell-leukemia-and-relapsed-refractory-multiple-myeloma. Published April 2014. Accessed March 24, 2015.

Adams S. Is this a miracle cancer vaccine? Scientists hail breakthrough treatment as a &lsquo;game changer.&rsquo; http://www.dailymail.co.uk/health/article-3005816/Is-miracle-cancer-vaccine-Scientists-hail-breakthrough-treatment-game-changer.html#ixzz3VDo3tEFO. Published March 21, 2015. Accessed March 24, 2015.

ClinicalTrials.gov. Phase II study of adjuvant WT-1 analog peptide vaccine in MPM patients after MSK10-134. https://clinicaltrials.gov/show/NCT01890980. Updated March 16, 2015. Accessed March 24, 2015.

Seattle Cancer Care Alliance. T-cell therapies. http://www.seattlecca.org/diseases/immunotherapy-t-cell-therapies.cfm. Accessed March 24, 2015.

Bar M. Researchers aim to improve blood cancer outcomes with engineered T-cell treatments. http://www.onclive.com/publications/obtn/2013/december-2013/researchers-aim-to-improve-blood-cancer-outcomes-with-engineered-t-cell-treatments/1. Published January 2, 2014. Accessed March 24, 2015.

ITOC 2. 2nd Immunotherapy of cancer conference programme book. http://itoc-conference.eu/files/2014/05/ITOC2-Programme-book-FINAL-2.pdf. Accessed March 24, 2015.

Physician&rsquo;s Education Resources. CME Conferences. http://www.gotoper.com/conferences/asco15/meetings/targeting-pathways-efficacy-and-combinations. Accessed March 24, 2015.

Immunotherapy vaccine approaches that involve harvesting a patientâ€™s dendritic cells and priming them to recognize a tumor-specific antigen before injecting them back into the patient to activate a T-cell response against the tumor have achieved encouraging but limited success.

Researchers Explore Novel Approaches to Boost Immunotherapy Vaccines

Growth in healthcare spending in the United States continues to outpace growth in European countries that enjoy a similar standard of living. Compared with the nations that make up the Organisation for Economic Co-operation and Development, the US spends a higher percentage of its gross domestic product on health and ranks first in per capita spending on healthcare and pharmaceuticals.

Cancer is one area where healthcare costs continue to soar in the US and abroad.

In 2011, the annual cost of cancer care in the US was estimated at around $124 billion and was projected to top $173 billion by 2020.

Although oncologists do not question the value of prolonging lives and relieving suffering, some are questioning how much proverbial bang for the buck patients are receiving from the new oncology drugs that have driven much of the growth in per-patient costs.

The monthly price tag for 9 of the 12 new cancer drugs the US Food and Drug Administration (FDA) approved in 2012 exceeded $10,000.3 In looking at targeted drugs, Kantarjian et al reported annual costs ranging from $61,000 per year for lapatinib to $270,000 per year for brentuximab.

Only 3 of the 12 cancer drugs approved in 2012 prolonged survival; and of those 3 drugs, only 1 extended survival by more than 2 months.

As the population ages, the number of US cancer survivors is expected to grow from 14.5 million in 2014 to 18 million in 2020an almost 25% increase.

As a result, many oncologists fear that the current cost of treating cancer in the US is unsustainable.

Two Dartmouth researchers decided to analyze whether or not the US reaps greater benefit from spending more on cancer care than its counterparts in Western Europe.

Using demographic data and national data on healthcare expenditures for 20 Western European countries plus the US, Soneji and Yang estimated the amount each country spent between 1982 and 2010 for each of 12 cancer types. Next, they looked at trends in cancer mortality for each country.

In a press release at the Dartmouth website, lead author Samir Soneji, PhD, an assistant professor at Dartmouth's Geisel School of Medicine and the Institute for Health Policy & Clinical Practice, Dartmouth College, Lebanon, Pennsylvania, described the significance of the findings. "Our results suggest that cancer care in the US did not always avert deaths compared to Western Europe and, when it did avert deaths, it often did so at substantial cost," said Soneji.

"The greatest number of deaths averted occurred in cancers for which decreasing mortality rates were more likely to be the result of successful prevention and screening rather than advancements in treatment."

found that the US spent $435 billion more than Western Europe on breast cancer, resulting in 67,000 fewer breast cancer deaths, for an incremental cost to quality of life-year (QALY) saved of $402,000. For colorectal cancer, the US spent $326 billion more than Western Europe, averting 265,000 deaths, for an incremental cost-to-QALY ratio of $110,000. The $435 billion in increased spending on prostate cancer in the US averted 60,000 deaths for a cost-to-QALY ratio of $1,979,000. For lung cancer, the United States spent $406 billion more than Western Europe, yet counted 1,120,000 more deaths. This corresponded with an estimated loss per QALY of $19,000.

Historically, the benchmark for assessing value has long been $50,000 per QALY, although some have suggested raising the QALY threshold in the US to $100,000 or $150,000, or as high as $300,000.9 However, Soneji and Yang&rsquo;s study shows that the incremental cost per QALY in the US for several of the cancers evaluated would have exceeded even these higher thresholds.

Table. Deaths Averted and Cost Per QALY Saved in the United States by Cancer Type

In trying to determine reasons for the differences in mortality between the US and Western Europe for some cancers, the researchers found earlier adoption of trastuzumab in the US may have contributed to the lower breast cancer mortality rate but that greater reliance on mammography was unlikely to have played a role.7 Declines in prostate cancer deaths in the US and Europe were likely attributable to treatment advances, but the reason for the lower prostate cancer mortality rate in the US was unclear. Heavier use of colorectal cancer screening in the US appeared to account for the nation&rsquo;s much lower mortality rate for this cancer. The US also averted 621,820 more stomach cancer deaths than Western Europe, which the authors suggested may be due to lower rates of Helicobacter pylori infection and more sanitary food preparation in the country. The incremental cost-to-QALY ratio in stomach cancer was $4,635, well within the $50,000/QALY threshold. Other cancers where higher US spending did not avert deaths included melanoma, non-Hodgkin lymphoma, and leukemia. Overall, the study showed spending more on treatment did not always translate to better outcomes. However, increased spending on screening and prevention typically provided significant benefits for patients at a more favorable cost-to-QALY ratio.

As cancer therapy shifts from monotherapy regimens to combinations of drugs designed to inhibit different targets within a tumor simultaneously or to regimens that combine a targeted therapy with immunotherapy, the additional costs may help drive the growing burden of healthcare in the US to unsustainable levels.

Groups like the American Society of Clinical Oncology (ASCO) and the American Board of Internal Medicine Foundation are encouraging all physicians to include cost-effectiveness as a factor in planning treatment now, before care becomes unaffordable.

As ASCO notes on its website, "We should recognize that best use of limited resources does not have to necessarily compromise optimal treatment of every patient. The two goals are parallel and not in opposition."

OECD. OECD Health Statistics 2014: How does the United States compare? http://www.oecd.org/unitedstates/Briefing-Note-UNITED-STATES-2014.pdf. Accessed March 10, 2015.

Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. Projections of the Cost of Cancer Care in the United States: 2010-2020.

Kantarjian HM, Fojo T, Mathisen M, et al. Cancer drugs in the United States: Justum pretiumthe just price.

ASCO in action brief: value in cancer care. http://www.asco.org/advocacy/asco-action-brief-value-cancer-care. Published Janaury 21, 2014. Accessed March 10, 2015.

Experts in Chronic Myeloid Leukemia. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts.

American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2014-2015. Atlanta: American Cancer Society; 2014.http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-042801.pdf. Accessed March 10, 2015.

Soneji S, Yang J. New analysis reexamines the value of cancer care in the United States compared to Western Europe. Health Aff (Millwood). 2015;34:390-397.

US spends more on cancer care, saves fewer lives than Western Europe [press release]. http://cancer.dartmouth.edu/about_us/newsdetail/73137. Published March 2, 2015. Accessed March 10, 2015.

Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness--the curious resilience of the $50,000-per-QALY threshold.

Growth in healthcare spending in the United States continues to outpace growth in European countries that enjoy a similar standard of living.

Spending More for Cancer Care Does Not Reduce Mortality

Harold Varmus, MD, may be stepping down as director of the National Cancer Institute (NCI) at the end of March, but in an interview with

he made it clear that he is not retiring. On April 1, he assumes a new position as Lewis Thomas University Professor of Medicine at Weill Cornell Medical College, where he will continue working to unravel the mysteries of cancer biology. Varmus has also agreed to assist the New York Genome Center as a senior associate core member in advocating for greater use of cancer genomics throughout New York.

Varmus and his colleague J. Michael Bishop, MD, received the Nobel Prize for Physiology or Medicine in 1989 for their breakthrough discovery more than a decade earlier that showed the oncogenes in retroviruses were acquired from the normal cells of a host and corrupted as the virus incorporated these proto-oncogenes into its own genome. In essence, they revealed that a cell&rsquo;s normal genes are capable of transforming into cancer-causing genes, often in response to cell damage. Over the next several decades, researchers built on that seminal discovery to usher in an era of precision medicine in oncology.

&ldquo;Precision medicine, at its base, is about diagnosticspeople tend to forget that,&rdquo; said Varmus. &ldquo;What precision medicine does is allow us to frame the categorization of the disease in a new way based on the molecular properties of disease tissue. For cancer, that means looking at a cancer cell and determining why it behaves the way it does.&rdquo;

Varmus added that this involves analyzing the cell for mutations, changes in gene expression, and other evidence of alterations that affect the performance of the genome.

&ldquo;When we do that, we find there are commonalities among cancers that arise in different organs, and yet vast differences in some cancers that arise in the same organ.&rdquo; He explained that once you have identified the genetic damage that affects cell behavior, you need to figure out how to target it. &ldquo;It&rsquo;s not determining that a tumor is adenocarcinoma of the lung, but is instead determining that it is

-mutant lung cancer that tells you that you should do something about the

President Barack Obama has said he plans to direct $70 million in his 2016 budget to the NCI for his Precision Medicine Initiative.

Varmus pointed out that &ldquo;the president prepares his list of items for us to do, but of course he does not give out the money; Congress can choose to give some or all of the money, or they can choose to give the money but not label it with the president&rsquo;s initiatives.&rdquo; However, according to Varmus, the NCI had already voted to allot a substantial sum of its funds for precision medicine.

&ldquo;It is in our plans to expand our efforts in basic science, informatics, and genomics.&rdquo; The exceptional responder program is one example of the NCI&rsquo;s efforts to advance precision medicine. &ldquo;In the past, most trials were done by pooling patients who have a cancer that arises in a certain organ, like bladder cancer or lung cancer or brain cancer. Those patients represent a very heterogeneous mix, and many of those participants had cancers that were very different from the others,&rdquo; Varmus said.

He compares these early trials to conducting a clinical trial for pneumonia, which can be caused by different strains of bacteria, without wondering what the bacterium was. &ldquo;What you want is a precise diagnosis. In this case, we are going back to the old trials and looking for patients who had a beneficial effect from a drug in a study in which the drug generally didn&rsquo;t work. We&rsquo;re taking those tumors, when available, and looking at those genetic abnormalities and trying to figure out why it worked.&rdquo; Varmus said that the NCI has received material for more than 100 patients thus far.

In a letter to the NCI community announcing his resignation as director, Varmus mentioned the &ldquo;fiscal duress&rdquo; he faced during his 5-year tenure.

President Obama recently submitted his proposed 2015 budget for the National Institutes of Health to Congress for consideration, which includes a small increase for the NCI. When Varmus was asked how it might affect oncology research programs should Congress not grant the full amount President Obama has requested for the NCI&rsquo;s 2015 budget, he said, &ldquo;We need money to do these things, so obviously the dilemma for us would be how much obligation are we under to do what the president asked us to do if we don&rsquo;t get the extra money to do it?&rdquo;

In dealing with ongoing budget challenges over the past 5 years, Varmus and his team strived to make the NCI more efficient, improve the grant-making process, and further the agency&rsquo;s mission of advancing cancer research and reducing the burden of cancer worldwide. For example, Varmus launched the Provocative Questions initiative, which bestows grants on researchers searching for an answer to any of 24 important questions about cancer. Answering just one of these questions could lead to tremendous advances in the understanding of cancer, but because the rewards may be less immediate, research on these topics is poorly funded, according to Varmus.

Although CRISPR technology is not a result of the Provocative Questions program and has applications beyond oncology, Varmus likes to use CRISPR as an example of &ldquo;something that was totally unexpected, made possible by making an investment in an abstruse biological phenomenon.&rdquo; He added, &ldquo;CRISPR probably would not have been studied if some enlightened funding agency was going to make an investment.&rdquo; Under Varmus, the NCI also established the NCI Center for Global Health, to support cancer research in low- and middle-income countries; the Center for Cancer Genomics; and the Outstanding Investigator Award, a 7-year grant designed to provide investigators with greater stability in pursuing their work.

The NCI continues to collaborate with the private sector on important initiatives. &ldquo;We have numerous collaborations in this industry. Some are run through a third party, like the Foundation for the NIH. Some are arranged through profit and research development agreements,&rdquo; Varmus said. &ldquo;We have a well-known trial called MATCH that is going to depend on donations of drugs from companies. We have another trial that was launched some months ago through the NIH called the Lung-MAP study, which involves genetic analysis for squamous cell carcinoma. Companies have put up much of the funding for it; the Foundation for the NIH put up some of the money, and the research sites will be contributing.&rdquo;

Throughout his storied career in oncology, Varmus has left a trail of successes. His departure from the NCI will no doubt be a loss for the agency. Fortunately, however, the world will continue to benefit from his ongoing involvement in oncology research and his advocacy for more research funding, collaboration, and openness; and for more precise medicine that will ultimately lead to improved outcomes for patients with cancer.

Fact sheet: President Obama&rsquo;s Precision Medicine Initiative. http://www.whitehouse.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative. Published January 30, 2015. Accessed March 6, 2015.

Varmus H. A letter to the NCI community. http://www.cancer.gov/aboutnci/director/messages/harold-varmus-resignation. Published March 4, 2015. Accessed March 5, 2015.

Harold Varmus, MD, may be stepping down as director of the National Cancer Institute (NCI) at the end of March, but in an interview with Targeted Oncology, he made it clear that he is not retiring.

Varmus Leaving NCI to Move Precision Medicine in Oncology Forward on Other Fronts

Understanding Crosstalk in Tumor Microenvironment Could Lead to New Precision Medicine Approaches

Many patients with nonsmall cell lung cancer (NSCLC) have no identifiable mutations, and therefore their disease cannot be managed with targeted treatments. These patients often experience disease progression despite chemotherapy. However, a study led by investigators at Weill Cornell Medical College used a new approach to examine crosstalk between cancer cells and cells in the microenvironment in NSCLC. Instead of looking at the tumor as a whole, the researchers used deep sequencing of RNA to analyze individual cell populations isolated from NSCLC specimens, an approach that could someday lead to new treatments for patients with NSCLC.

To analyze the enormous amount of data generated through the RNA sequencing step, the research team had to develop a new computational modeling program. They found no existing program was capable of revealing all the pathways that multicellular-stromal components and tumor epithelial cells use to communicate. The program they developed, called Cell Cell Communication (CCC) Explorer, decodes gene arrangements in these cellular networks. To test the reliability of CCCExplorer at predicting crosstalk pathways in macrophages, monocytes, neutrophils, tumor cells, and epithelial cells, the investigators manipulated some of the identified pathways in animal models of lung cancer and human lung cancer tissue. Their results confirmed the CCCExplorer predictions and indicated that the program may be useful in identifying new targets for treatment in the tumor microenvironment. The team recently published their findings in

had an opportunity to interview Vivek Mittal, PhD, associate professor of cell and development biology at Weill Cornell Medical College, New York, about these findings.

: What is new about your findings regarding how the tumor communicates with its microenvironment?

The tumor microenvironment is an emerging field in oncology and is currently being intensely investigated. The tumor microenvironment is heterogeneous, composed of different cell populations. These are groups of normal cells in our body that participate in normal physiological functions and are somehow reprogrammed by the cancer cells to promote tumor growth.

We wanted to determine how the tumor cells reprogram each cell population in the microenvironment at a molecular level. Once we know this, we can then begin to determine how, in turn, the reprogrammed microenvironment contributes to tumor progression.

Nobody has worked before to understand reprogramming of the microenvironment at a global level. To understand how all the different cells are reprogrammed by one tumor, we decided we needed to fractionate the tumor into specific individual cellular populations and examine each one on a molecular level. If you study the tumor as a whole, you will not be able to see how the tumor affects all the different cell populations in the microenvironment. It is like your neighborhoodyou have to understand each sector of the community first before you can determine how the whole neighborhood functions.

How does the microenvironment contribute to tumor growth or disease spread?

The tumor activates the cell populations in the microenvironment so that they secrete tumor-promoting growth and signaling factors. Each of these factors acts as a key and binds to their specific receptors (the lock) on the tumor cells. This activates molecular pathways inside the tumor cells, which make the tumor cells divide and grow rapidly.

To give you an example, everyone is familiar with the recent success of immunotherapy and how the immune cells fight disease activity. In the tumor microenvironment, the cancer cells engage the brakes on the immune cells to make the immune cells dysfunctional. Since we now know the molecular nature of these brakes, therapies have been developed to disengage them. Thus, we can target them with drugs and take the blocks off the brakes, allowing a stronger immune response.

We are trying to figure out how the tumor blocks or activates these cell populations through crosstalk that occurs between the tumor cells and the cells in the microenvironment. This crosstalk is very important. So far we have known bits and pieces of it, but we need to understand it at the global level, in the whole tumor. It is like being aware of only a few conversations in a cocktail partyknowing all the conversations that took place at the cocktail party would give you a better understanding of what transpired.

Could you explain more about how you achieved your findings and what CCCExplorer is?

Our idea was that you have to split the tumor into different cell communities and then perform genomic analysis on each community. Once we had all the genomic data for all the cell populations, we said, &ldquo;What can we do with these data to understand the nature of the tumor? How can we mine them to determine how the cells talk to each other?&rdquo;

Since this was the first time taking this approach, we had no way to analyze this multicellular genomic data. We collaborated with a group of computational biologists from the Methodist Hospital in Houston, Texas, and spent 8 or 9 months engaging in our own crosstalkbetween experimental biologists and computational biologists&mdash;to develop a model that allows you to identify the different cell communities and how they interact with the tumor. That is what CCCExplorer does.

Do your findings have any implications for the growing reliance on targeted molecular therapies to treat cancer?

What we now have are many unexplored targets in the microenvironment that potentially have functional significance. We still have to determine experimentally what these cell populations do in the microenvironment and how they help the tumors progress.

These are normal cells, and you do not target normal cells. But the tumor has hijacked or hypnotized them, so they are in an abnormal activated state. Abnormal stromal cells in the tumor microenvironment, for example, have different gene expression patterns than normal stromal cells. We want to target the cells in their activated state; and, more importantly, we want to target the crosstalk pathways they use to engage with the tumor cells. Drugs that target these activated cells could work alone or with standard care therapy.

Many cancers do not have a known driver mutation, or if they do there are no drugs to target them, and chemotherapy is the only treatment. Molecular analysis of the microenvironment like we did can identify new molecular targets for treatment.

Do different cancers have the same aberrant cell populations in the microenvironment? For example, would the cell populations in the breast cancer microenvironment differ from the cell populations you found that were active in the lung cancer microenvironment?

We have not done this kind of detailed molecular analysis in breast cancer, but we know many of the same cells are involved. However, while we expect to find some common mechanisms, there is a strong likelihood that some populations will be different and some mechanisms will be different for each cancer.

Do genetic mutations have any role in determining the make-up of these cell populations in the tumor environment?

Recent studies have begun to indicate that oncogenes can modulate the microenvironment. Therapy can also change the microenvironment, leading to tumor resistance and progression. For example, the microenvironment can elicit resistance to a therapy. With chemotherapy resistance in lung or breast cancer, we have begun to learn that combining chemotherapy with a drug that targets the resistance aspect of the microenvironment can elicit a better overall response.

We have only validated a few of the molecular targets we identified. Our goal is to experimentally validate may of the computationally predicted crosstalk pathways. Importantly, we have also performed similar analyses in human lung cancer. The idea is to compare the crosstalk findings from human and mouse studies to identify common pathways and to perturb these pathways genetically or with drugs in the mouse model of lung cancer to determine their tumor-promoting function. Our preliminary analysis looks promising and suggests that the pathways we are identifying might be candidates for therapy development.

The tumor microenvironment field is moving in one direction right now, but there is a lot more to do. As tumor status changes, how do tumor-specific driver genes influence these pathways? When the tumor is exposed to chemotherapy, what changes in the microenvironment pathway can we target to destroy the tumor?

Imagine the electric grid in New York City, with wires running from one place to another. If you block the signal in one wire, lights go off in one part of the city. Our goal is to find key nodes, so that their interruption can lead to shutting down lights in the whole city. We need to find the most important circuits in the tumor&rsquo;s &ldquo;grid&rdquo; that will allow us to shut down the tumor completely.

Choi H, Sheng J, Wong STC, Mittal V, et al. Transcriptome analysis of individual stromal cell populations identifies stroma-tumor crosstalk in mouse lung cancer model.

Many patients with nonâ€“small cell lung cancer (NSCLC) have no identifiable mutations, and therefore their disease cannot be managed with targeted treatments.

Understanding a Tumor's Microenvironment

The standard clinical trial model for a new drug presents many challenges. Trials are expensive, costing anywhere from $300-600 million.

Busy practitioners are sometimes reluctant to refer their patients to off-site clinical trials because of cumbersome requirements and lost revenue. Patients may be unaware of available trials, live too far from a study site to consider participating, or live just far enough away that travel and time costs would impose significant burdens, especially for someone dealing with an illness like cancer.

Also, some patients are unwilling to exchange their regular provider for someone new.

Novartis Oncology hopes to overcome many of these challenges with the innovative Signature Clinical Trial program, which &ldquo;bring[s] the &lsquo;Protocol to the Patient.&rsquo;&rdquo;

Signature is a series of phase II proof-of-concept trials, each with a specific molecular target.

The program was designed to provide patients with faster, more convenient access to novel targeted oncology drugs, thus providing researchers with data on a drug&rsquo;s safety and effectiveness much sooner than a conventional trial.

Under the Signature program, instead of opening a fixed number of sites at specified locations, Novartis will establish a trial site wherever an eligible patient is identified.

Once a physician determines that a patient&rsquo;s cancer has a one of the qualifying mutations, he or she calls a Novartis Signature trial administrator to discuss opening a site.

Any &ldquo;research-experienced site in the United States accepting [the Novartis] study model&rdquo; is able to participate.

Normally, it takes around 8 months to get a trial site operational

; Novartis expects it to take no more than 3 weeks to open a Signature site.

Whereas a traditional trial site must enroll multiple patients, a Signature site has no requirement to enroll anyone beyond the initial patient.

Another unconventional aspect of Signature is its tissue-agnostic approach. Frequently in oncology, a clinical trial for a targeted drug enrolls patients who share the same cancer type. For example, trastuzumab (Herceptin) was first evaluated in and approved for patients with breast cancer. Later, it was studied in and approved for patients with gastric cancer. The Signature trials will include patients with any type of cancer who test positive for a specific mutation.

Because the patient was already pre-identified as eligible, no further screening is required.

EGFR, PDGFR, VEGF, cKIT, FLTC CSFR1, Trk, RET mutations or translocations

Novartis currently has 9 Signature trials under way (8 in oncology;

As with conventional trials, the Signature trials require informed consent. These trials include a centralized Institutional Review Board. Each compound being evaluated is covered under a separate protocol.

To ensure the safety of the doses being tested, phase I dose-finding trials were conducted for each compound. Patients enrolled in Signature receive the test drug for 16 weeks. The primary endpoint is clinical benefit ratethe percentage of patients who achieve a response or have stable disease at the end of the study. At a presentation at the 2014 American Society of Clinical Oncology (ASCO) annual meeting, an abstract reported that &ldquo;73 patients have been consented at 46 network, academic, and community sites.&rdquo;

ASCO is launching a similar program called the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

TAPUR, which is the first clinical trial ASCO has ever initiated, will allow physicians to enroll patients who they have identified as having one of the qualifying molecular targets. During the trial, patients will receive an approved drug off label. ASCO plans to release a list of eligible drugs matched to specific targets. The primary endpoint in TAPUR is response rate, but other safety and efficacy data will be collected.

As companies and institutions implement new approaches to clinical trial design in the United States, it is unclear how the US Food and Drug Administration will respond to data obtained through these nonstandard trials. However, less than half of oncology patients discuss clinical trials with their physician, and less than 10% enroll in a clinical trial.

Signature, TAPUR, and similar programs aim to improve these numbers and allow more patients to reap the benefits of precision medicine.

Institute of Medicine (US) Forum on Drug Discovery, Development, and Translation. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Washington, DC: National Academies Press (US); 2010.

Novartis Oncology. About Signature. https://www.signaturetrial.com/en/hcp/AboutSignature. Published August 2014. Accessed February 16, 2015.

Novartis Oncology. Signature trial program  frequently asked questions. https://www.signaturetrial.com/en/hcp/FAQ#HowManyProtocols. Published August 2014. Accessed February 16, 2015.

Novartis Oncology. Referring a patient. https://www.signaturetrial.com/en/hcp/Refer. Published August 2014. Accessed February 16, 2015.

Slosberg ED, Kang B, Beck JT, et al. The signature program, a series of tissue-agnostic, mutation-specific signal finding trials.

Tufts, CSDD. Survey results of start-up cycle times. http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/article/articleDetail.jsp?id=796689. Published November 1, 2012. Accessed February 16, 2015.

Novartis Oncology. Signature site map. https://www.signaturetrial.com/en/hcp/SiteMap. Published August 2014. Accessed February 16, 2015.

New ASCO study aims to learn from patient access to targeted cancer drugs off-label. http://www.asco.org/advocacy/new-asco-study-aims-learn-patient-access-targeted-cancer-drugs-used-label. Published November 21, 2014. Accessed February 16, 2015.

Unger JM, Hershman DL, Albain KS, et al. Patient income level and cancer clinical trial participation.

Novartis Oncology hopes to overcome many of these challenges with the innovative Signature Clinical Trial program, which â€œbring[s] the â€˜Protocol to the Patient.â€™â€