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Wednesday, October 17, 2018

Researchers at Dana-Farber Cancer Institute are seeking participants in a new study, funded as part of the Stand Up To Cancer Multiple Myeloma Dream Team, to identify people with conditions that are precursors of multiple myeloma and track their health over time.

The study, dubbed PROMISE, will help scientists track the molecular changes that occur as precursor conditions progress to myeloma. This information will be critical in the development of drugs that prevent the disease from advancing and improve patients' survival.

Almost all patients diagnosed with multiple myeloma have had one of two precursor conditions: monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma. Because there is no routine screening for these conditions, and because they generally don't produce symptoms, they often go undiagnosed. Even when they are diagnosed, current practice is to monitor patients with a "watch and wait" approach and begin treatment only after myeloma symptoms develop.

"Our hope is that by screening and identifying the precursor conditions early, we can understand the molecular signs of progression to myeloma, and develop therapies that will replace 'watch and wait' and make myeloma a preventable disease," said the study's principal investigator, Irene Ghobrial, MD, of Dana-Farber.

The study is open to two groups of individuals between the ages of 45 and 75 who have been identified to be at high risk of multiple myeloma and its precursor conditions:

  • African Americans, who are three times more likely than Caucasians to develop the myeloma precursor condition MGUS, also known as smoldering myeloma;
  • People with a first-degree relative (a parent, sibling, or child) with a plasma cell disorder such as multiple myeloma.

Participants will complete an online health questionnaire, provide blood samples periodically for analysis, and submit updated health information periodically. Participants whose blood samples test positive for a myeloma precursor condition will be assisted in scheduling an appointment with a hematologist/oncologist. They will also be asked to submit health information and blood samples every 3-6 months and may be eligible for clinical trials exploring treatments to prevent progression. These samples will be analyzed for molecular signs indicating the risk of disease progression.

Initial participation in the trial is online or by mail. Local travel for blood draw is required. Testing will be performed at each participant's local Quest Diagnostics laboratory. To sign up for the study, please visit www.promisestudy.org.

Members of the Dream Team include Timothy Rebbeck, PhD, of Dana-Farber; Ivan M. Borrello, MD, of Johns Hopkins University School of Medicine; Joseph Mikhael, MD, of the Mayo Clinic Arizona; Jeremiah A. Johnson, PhD, of MIT; Lorelei Ann Mucci, MPH, DSc, of the Harvard T.H. Chan School of Public Health; and Gad Getz, PhD and Viktor A. Adelsteinsson, PhD, of the Broad Institute.

Thursday, October 11, 2018

Cancer needs energy to drive its out-of-control growth. It gets energy in the form of glucose, in fact consuming so much glucose that one method for imaging cancer simply looks for areas of extreme glucose consumption -- where there is consumption, there is cancer. But how does cancer get this glucose?

A recently published University of Colorado Cancer Center study shows that leukemia undercuts the ability of normal cells to consume glucose, thus leaving more glucose available to feed its own growth (Cancer Cell 2018; doi:10.1016/j.ccell.2018.08.016).

"Leukemia cells create a diabetic-like condition that reduces glucose going to normal cells, and as a consequence, there is more glucose available for the leukemia cells. Literally, they are stealing glucose from normal cells to drive growth of the tumor," said Craig Jordan, PhD, investigator at University of Colorado Cancer Center, Division Chief of the Division of Hematology and the Nancy Carroll Allen Professor of Hematology at the University of Colorado School of Medicine.

Key Findings

Like diabetes, cancer's strategies depend on insulin. In diabetes, either the pancreas under-produces insulin or tissues cannot not respond to insulin and so cells are left starved for energy while glucose builds up in the blood. The current study shows that leukemia goes about creating similar conditions of glucose buildup in two ways.

First, tumor cells trick fat cells into over-producing a protein called IGFBP1. This protein makes healthy cells less sensitive to insulin, meaning that when IGFBP1 is high, it takes more insulin to use glucose than it does when IGFBP1 is low. Unless the supply of insulin goes up, high IGFBP1 means that the glucose consumption of healthy cells goes down. (This protein may also be a link in the chain connecting cancer and obesity: The more fat cells, the more IGFBP1, and the more glucose is available to the cancer.)

Of course, cancer has a second strategy that ensures insulin production does not go up to meet the need created by increased IGFBP1. In fact, cancers turn insulin production down. In large part, they do this in the gut.

"In the course of doing this systemic analysis, we realized that some of the factors that help regulate glucose are made by the gut or bacteria in the gut. We looked there and found that the composition of the microbiome in leukemic animals was different than in control mice," Jordan explained.

One major difference in the guts of leukemic mice was the lack of a specific kind of bacteria known as bacteroids. These bacteroids produce short-chain fatty acids that in turn feed the health of cells lining your gut. Without bacteroids, gut health suffers. And the current study shows that without bacteroids, gut health suffers in ways that specifically aid cancer.

One way is the loss of hormones called incretins. When blood glucose gets high, for example after you eat, your gut releases incretins, which tamp down blood glucose, reducing it back into the normal range. Working through the gut, leukemia inactivates these incretins, allowing blood glucose to remain higher than it should. Leukemia also nixes the activity of serotonin. Serotonin is essential for the manufacture of insulin in the pancreas, and by attacking serotonin, leukemia reduces insulin production (and thus, down the line, glucose use).

The result of less insulin secretion and less insulin sensitivity is that cancer undercuts healthy cells' use of insulin from both sides: healthy cells need more insulin, just as there is less insulin available. Less insulin use by healthy cells leaves more glucose for the cancer.

"It's a classic parasite trick: Take advantage of something the host does and subvert it for your own purposes," Jordan said.

Interestingly, just as a parasite might eat a host's food leading to malnourishment, cancer's energy theft may play a role in the fatigue and weight loss common in cancer patients.

"The fairly prevalent observation is that cancer patients have a condition called cachexia, basically wasting away -- you lose weight. If cancers are inducing systemic changes that result in depletion of normal energy stores, this could be part of that story," Jordan noted.

Ser-Tri Therapy

However, Jordan and colleagues including first author Haobin Ye, PhD, not only showed how leukemia dysregulates healthy cells' glucose consumption, but also showed how to "re-regulate" this consumption.

"When we administered agents to recalibrate the glucose system, we found that we could restore glucose regulation and slow the growth of leukemia cells," Ye said.

These agents were surprisingly low-tech. One was serotonin. Another was tributyrin, a fatty acid found in butter and other foods. Serotonin supplementation replaced the serotonin nixed by leukemia and tributyrin helped to replace the short-chain fatty acids that were absent due to loss of bacteroids.

The group calls the combination Ser-Tri therapy. And they show that it is more than a theory. Ser-Tri therapy led to the recovery of insulin levels and reduction of IGFPB1. And leukemic mice treated with Ser-Tri therapy lived longer than those without. Twenty-two days after leukemia was introduced in mice, all of the untreated mice had died, while more than half of the mice treated with Ser-Tri were still alive.

The continuing line of work shows that cancer may depend on the ability to out-compete healthy cells for limited energy. Healthy tissues have strategies to regulate insulin, glucose, and other factors controlling energy consumption; cancer cells have strategies to subvert this regulation with the goal of making more energy available for their own use.

"We now have evidence that what we observed in our mouse models is also true for leukemia patients." Ye explained.

Understanding these mechanisms that cancer uses to unbalance the body's system of energy in their favor is helping doctors and researchers learn to thumb the scale in favor of healthy cells.

"This furthers the notion that you can do things systemically to disfavor leukemia cells and favor normal tissue," Jordan concluded. "This could be part of limiting growth of tumors."

Monday, October 1, 2018

Jim Allison, PhD, Chair of Immunology and executive director of the Immunotherapy Platform at The University of Texas MD Anderson Cancer Center, today was awarded the 2018 Nobel Prize in Physiology or Medicine for launching an effective new way to attack cancer by treating the immune system rather than the tumor. Allison is the first MD Anderson scientist to receive the world's most preeminent award for outstanding discoveries in the fields of life sciences and medicine.

"By stimulating the ability of our immune system to attack tumor cells, this year's Nobel Prize laureates have established an entirely new principle for cancer therapy," the Nobel Assembly of Karolinska Institute in Stockholm noted in announcing the award to Allison and Tasuku Honjo, MD, PhD, of Kyoto University in Japan.

"I'm honored and humbled to receive this prestigious recognition," Allison said. "A driving motivation for scientists is simply to push the frontiers of knowledge. I didn't set out to study cancer, but to understand the biology of T cells, these incredible cells to travel our bodies and work to protect us."

Allison started his career at MD Anderson in 1977, arriving as one of the first employees of a new basic science research center located in Smithville, Texas. He was recruited back to MD Anderson in November 2012 to lead the Immunology Department and to establish an immunotherapy research platform for MD Anderson's Moon Shots Program.

"Jim Allison's accomplishments on behalf of patients cannot be overstated," said MD Anderson President Peter WT Pisters, MD. "His research has led to life-saving treatments for people who otherwise would have little hope. The significance of immunotherapy as a form of cancer treatment will be felt for generations to come."

The prize recognizes Allison's basic science discoveries on the biology of T cells, the adaptive immune system's soldiers, and his invention of immune checkpoint blockade to treat cancer.

Allison's crucial insight was to block a protein on T cells that acts as a brake on their activation, freeing the T cells to attack cancer. He developed an antibody to block the checkpoint protein CTLA-4 and demonstrated the success of the approach in experimental models. His work led to development of the first immune checkpoint inhibitor drug. Ipilimumab was approved for late-stage melanoma by the FDA in 2011.

His drug, ipilimumab, became the first to extend the survival of patients with late-stage melanoma. Follow-up studies show 20 percent of those treated live for at least 3 years with many living for 10 years and beyond, unprecedented results. Subsequent research has extended this approach to new immune regulatory targets, most prominently PD-1 and PD-L1, with drugs approved to treat certain types and stages of melanoma, lung, kidney, bladder, gastric, liver, cervical, colorectal, and head and neck cancers and Hodgkin's lymphoma. Clinical trials are underway in many other cancer types.

"I never dreamed my research would take the direction it has," Allison said. "It's a great, emotional privilege to meet cancer patients who've been successfully treated with immune checkpoint blockade. They are living proof of the power of basic science, of following our urge to learn and to understand how things work."

"Science advances on the efforts of many," Allison said. "A succession of graduate students, postdoctoral fellows and colleagues at MD Anderson, the University of California, Berkeley, and Memorial Sloan Kettering Cancer Center played important roles in this research."

Allison's ongoing leadership at MD Anderson focuses on improving knowledge of how these drugs work to extend the benefits of immunotherapy to more patients with more types of cancer. He continues his own research, focusing on the details of immune response to cancer and identifying new targets for potential treatment.

He also leads the immunotherapy platform for MD Anderson's Moon Shots Program, which conducts immune monitoring by analyzing tumor samples before, during and after treatment, aiming to understand why these drugs work for some patients but not for others. The platform works with more than 100 immunotherapy clinical trials at MD Anderson addressing a variety of cancers. The platform also collaborates with pharmaceutical companies to help them develop new drugs and combinations to better treat cancer.

"We need these drugs to work for more people," Allison said. "One challenge is that the clinical success has outrun our scientific knowledge of how these drugs work and how they might best be combined with other therapies to improve treatment and reduce unwanted side effects. We need more basic science research to do that."

Allison has collaboratively worked with scientists around the globe to expand the field of immunotherapy. Some of his leadership positions include serving as a co-leader of the Stand Up To Cancer-Cancer Research Institute Cancer Immunology Dream Team and as a director of the Parker Institute for Cancer Immunotherapy (PICI). Allison also is deputy director of the David H Koch Center for Applied Research of Genitourinary Cancers at MD Anderson and holds the Vivian L. Smith Distinguished Chair in Immunology.

Crucial funding for his research over the years has come from the National Institutes of Health, particularly the National Cancer Institute, the Cancer Prevention & Research Institute of Texas, Howard Hughes Medical Institute, the Cancer Research Institute, Prostate Cancer Foundation, Stand Up to Cancer and PICI.

Allison will be honored at Nobel ceremonies in Stockholm in December. The Nobel Prize in Physiology or Medicine has been awarded 108 times to 214 Nobel Laureates between 1901 and 2017.


Tuesday, September 18, 2018

Clive Zent, MD, from Wilmot Cancer Institute offers a closer look at his recent research, "Management of melanoma in patients with chronic lymphocytic leukemia," which was featured in HemOnc Times' Research Minute. Learn more about the study and its potential clinical implications.

What prompted this research?

Skin cancers including malignant melanoma are known to be significantly more common in patients with chronic lymphocytic leukemia (CLL). We wanted to 1) determine the incidence and prevalence of melanoma in a stable regional CLL population and 2) assess the effectiveness of our policy of routine surveillance for skin cancers designed for early detection of melanomas to increase the rate of curative surgical treatment.

Can you describe the methodology?

This was an observational study using an established CLL database with 470 patients with CLL seen at the Wilmot Cancer Institute contributing 2,849 person-years of data.

What are the key findings?

Eighteen (3.8%) patients had 22 melanomas. Fourteen (3%) patients had invasive melanoma ( stage I)with a standardized incidence ratio of 6.3 (95% confidence interval 3.5-10.6) compared to an age and sex matched non-CLL SEER control population.

Most patients (n=14) were diagnosed with non-advanced stage melanoma and treated surgically. Four patients had advanced stage melanoma and one of these patients with progressive high-risk CLL (deletion of 17p13) had a sustained response (ongoing at 29 months from diagnosis of melanoma) on treatment with ibrutinib and pembrolizumab.

What (if any) are the limitations of this study?

  • This observational study included some retrospectively collected data that can be incomplete and less accurate.
  • The small number of patients with melanoma precludes more detailed analysis of the relationship between CLL and melanoma.
  • Doing the research at a referral center could have biased the results.

What are the implications of this research?

CLL patients are at significantly increased risk of malignant melanoma which can occur at any time during the course of their disease. Early detection of melanoma improves outcome. Regular skin evaluations by a dermatologist can lead to curative surgical therapy of non-advanced stage melanoma. Combination targeted therapy for patients with both CLL and advanced stage melanoma can be effective.

CLL patients need to be educated early and often about the increased risk of melanoma. Patients and their families need to learn how to decrease the risk of melanoma by avoiding excessive UV light exposure and active monitoring by a dermatologist supplemented by frequent self-examinations. ​

Tuesday, September 18, 2018

There has been significant success in the treatment of pediatric acute lymphoblastic leukemia (ALL) patients, however the same cannot be said about the adult population. Why is this case? Reasons include chemotherapy-related toxicities in adult patients as well as biological difference in pediatric disease.

Andrew Pham, MD, a hematology/oncology expert at Scripps Clinic in San Diego discusses the state of immunotherapy in ALL. Check out his insights below and read, "The Bold World of Immunotherapy for Acute Lymphoblastic Leukemia" in the September 20 issue of HemOnc Times to learn more!

"Current immunotherapies are extremely effective in terms of efficacy when compared to prior chemotherapies," Pham explained. "Generally, this is best demonstrated in the second-line setting once patients have relapsed; under these situations, chemotherapy has generally failed to produce a significant response.

"For these patients, immune therapies have shown to still be extremely effective," he explained, "specifically, CAR T-cell therapy has been shown to have remission rates of up to 80 percent, which is unprecedented, especially in the relapsed and refractory setting. However, these results come with a different slew of [adverse events], notably CRS and neurotoxicity, which have been well-documented."

Most Commonly Employed Immunotherapies Utilized in ALL

"In terms of practicality, currently, antibody-drug conjugate or BiTE therapy are most widely used for ALL in the relapse/refractory setting," Pham said. Regarding these therapies' shortcomings, he noted, "Significant toxicities are associated with these drugs, sometimes limiting their use. Notably, veno-occlusive disorder is widely associated with the use of inotuzumab ozogamicin and blinatumomab."

Recent Developments in CAR-T Therapy

"Much of the advances in CAR T-cell therapy thus far have been to combat the severe adverse effects; knowledge and management regarding CRS has grown substantially," Pham noted.

There are areas for further development for CAR-T therapy. "An aspect of which we have to further improve includes targeting mechanisms of resistance that have developed. A known mechanism of resistance has been the loss of CD19 or a truncated CD19 receptor, which renders CAR T cells ineffective," according to Pham. "The introduction of a CD22 CAR T-cell therapy may be the solution to this. In addition, current checkpoint inhibitors are now being incorporated to overcome checkpoint blockade that develops as another mechanism of resistance."

Recent Immunotherapy-Based Studies for ALL

"There are numerous clinical trials underway to look at the combination of different immunotherapies with upfront standard chemotherapy, including the use of inotuzumab ozogamicin and blinatumomab, usually in a sequential fashion with first-line therapy," Pham explained.

"In addition, these therapies are being evaluated in the consolidative setting as well," he continued. "CAR T-cell therapy, given its known toxicity and adverse side effects, is generally reserved for the relapsed/refractory disease setting and clinical trials are also available, further evaluating its usage."

Don't miss more insights from Dr. Pham. Read HemOnc Times now!