In year two, MD Anderson Moon Shots Program begins to spin off innovation

Improved surgical outcomes for ovarian cancer, expanded potential impact for new drugs, and a novel family outreach program to head off cancers fueled by known genetic risk mutations are among the early innovations of The University of Texas MD Anderson Cancer Center’s Moon Shots Program.

First-of-a-kind combination clinical trials; advanced molecular analysis to guide treatment and screening; and a focused program to gather, store, access and apply massive amounts of information to help patients and learn along the way also are unfolding.

“Our Moon Shots Program presses on to save more lives more quickly by cultivating powerful, efficient connections between vast new scientific knowledge and our efforts to improve patient care, protect those at risk and prevent cancer outright,” MD Anderson President Ron DePinho, M.D., said.

“Moon shots gather MD Anderson’s multidimensional expertise and tap remarkable new technologies to better deploy what we already know about cancer against these diseases and to contribute creative new answers to crucial challenges,” he said.

The program was launched in fall 2012 to accelerate the conversion of scientific discoveries into clinical advances and significantly reduce cancer deaths. The initial moon shots address melanoma, lung, prostate and breast/ovarian cancers as well as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML)/ myelodysplastic syndromes (MDS).

Execution and rocket science

Giulio Draetta, M.D., Ph.D., professor in Molecular and Cellular Oncology and co-director of the Moon Shots Program, characterizes the concepts underpinning the program with two themes: “Execution and rocket science.”

“This first wave of accomplishments reflects the moon shots’ emphasis on execution,” says Draetta. “It’s a matter of more efficiently applying what we already know about cancer to help our patients.”

“Rocket science enables our clinicians and scientists to make discoveries and clinical advances that really turn the world around,” he says. “Achieving that will require inventions yet to come. It will take time.”

Moon shots research benefits from innovative platforms in immunotherapy, genomics, proteomics, prevention and big data, as well as support by MD Anderson’s Center for Co-Clinical Trials and Institute for Applied Cancer Science.

Breast and Ovarian Cancer Moon Shot

A new protocol for determining which ovarian cancer patients should proceed to surgery upfront and which need presurgical chemotherapy has radically increased the rate of complete surgical removal of tumors, an accomplishment that improves patient survival.

Under the MD Anderson algorithm developed by the moon shot, a patient receives a less-invasive laparoscopic evaluation, during which two surgeons independently rank the cancer’s spread to other organs. The resulting score guides the treatment decision.

Previously, virtually all new patients had surgery to explore the extent of disease and to remove as much of it as possible. Worldwide, this practice results in 20 to 30 percent of these patients achieving “complete gross resection.” In the first 155 cases in which the algorithm was followed, complete resection was achieved 89 percent of the time.

Family outreach to head off cancer

The moon shot focused on high-grade serous ovarian cancer and triple-negative breast cancer offers genetic screening of all such MD Anderson patients for mutations in the BRCA 1 and 2 genes that elevate a person’s risk for either cancer. If a patient has these inherited mutations, the possibility that sisters, daughters and other relatives might have the same risk-elevating variations is increased.

The project, Making Cancer History® for the Family, works with patients who have BRCA mutations to contact and educate family members and offer them genetic screening. When BRCA mutations are found, and other risk factors are considered, the moon shot offers preventive options.

Breast and ovarian patients with BRCA1/2 mutations are offered participation in a clinical trial of drugs called PARP inhibitors, which target defects caused by BRCA mutations.

Lung Cancer Moon Shot
Leukemia drugs, lung cancer targets

The target and drug discovery group identified two drugs previously approved for treating leukemia that potentially hit lung cancer targets in some patients. A clinical trial of one, the targeted therapy ibrutinib, is underway for patients with treatment- resistant disease and specific mutations in the epidermal growth factor receptor (EGFR).

The moon shot screened 30 drugs approved by the U.S. Food and Drug Administration (FDA) for other cancers against 90 human non-small lung cancer cell lines to identify ibrutinib and another drug yet to go to trial. Approved drugs can be moved more quickly to clinical trial.

The drug screening platform is part of the moon shot’s larger effort to characterize lung cancer targets, match them to appropriate drugs and conduct targeted therapy clinical trials.

Better screening to catch cancer early

Screening former and present heavy smokers with a low-dose CT scan catches enough treatable, early- stage lung cancer to reduce deaths from the disease by 20 percent. About 90 percent of patients are cured when their cancer is identified at the earliest stage. Most lung cancer is only found much later, when treatment is markedly less successful.

One moon shot study opened locally this year addresses the major challenges in lung cancer CT screening: identifying who among the nation’s millions of current and former smokers needs to be screened and managing the false-positive rate of 96 percent of detected spots on the CT.

The study aims to identify and validate blood and airway biomarkers that would guide decision-making. Plans are in motion to extend the study nationally and internationally this year. The early detection project also will examine advanced imaging techniques, as well as risk modeling of demographic and behavioral factors.

Preventing teen tobacco use, helping smokers quit

The moon shot prevention program focuses on innovative ways to help teens avoid tobacco use and new, personalized approaches to smoking cessation.

Investigators extended the reach of their online anti-tobacco program called A Smoking Prevention Interactive Experience (ASPIRE) by connecting with a local clinic and a high school serving underprivileged areas of Houston where adolescents are at the highest risk for smoking. They are also developing a peer mentoring program that will connect high school and middle school students.

For smoking cessation, innovative studies are under development to advance personalized smoking cessation. Two trials will evaluate the use of genetic and neural biomarkers of reward sensitivity as indicators of treatment response. Another examines the best treatment options for people who fail to quit on either of two pharmacological smoking- cessation treatments.

Chronic Lymphocytic Leukemia Moon Shot
Easing out chemotherapy

The CLL Moon Shot is accelerating the transition from chemotherapy combinations for most patients to new targeted therapies and immunotherapy approaches.

MD Anderson CLL experts were instrumental in developing targeted therapies, including ibrutinib and idelalisib; both were FDA-approved in 2014 for CLL. These and other drugs such as the monoclonal antibody rituximab are inducing long-term responses in CLL patients with fewer and less harsh side effects than chemotherapy. Only 15 percent of newly treated patients with CLL at MD Anderson are treated with chemotherapy, down from 48 percent two years ago.

Moon shot investigators are leading a 208-patient clinical trial of ibrutinib versus ibrutinib plus rituximab that genomically analyzes each patient’s CLL before treatment, after treatment begins and, after the disease becomes resistant, if that occurs. Such specific genomic information will help the investigators understand how resistance develops and how to counter it.

They are also looking at additional combination therapies. The CLL Moon Shot opened three first-in- human clinical trials this year deploying state-of-the art engineered immune cells designed to find and destroy leukemia cells.

Two involve customized T cells, the attack cells of the adaptive immune system. The investigators collect a patient’s T cells, prime them to attack a specific surface protein on CLL cells, expand their number and then re-infuse the cells in the patient. The other transplants T cells derived from umbilical cord blood and customized against the same surface target.

The third uses natural killer cells, a less- targeted immune system killer cell, derived from umbilical cords, for transplant into patients. A fourth trial targets the T cells against the ROR1 protein, which is found only on CLL cells, and will open this year.

Prostate Cancer Moon Shot

Researchers have paired two drugs designed to thwart androgen receptor-driven, castrate-resistant prostate cancer in the first intent-to-cure clinical trial for a subgroup of prostate cancer patients.

Earlier studies identified a population of patients with castrate-resistant metastatic prostate cancer who might achieve a pathological complete response with the combination of abiraterone and enzalutamide. As of early October, 128 eligible patients were enrolled in the 180-patient phase II study.

The two drugs target the androgen receptor- testosterone pathway in different ways to reduce levels of the male hormone, which fuels most prostate cancers. They were initially considered rival drugs. Both are approved by the FDA as single agents for prostate cancer, but cancers eventually resist them.

Moon shots researchers found that the combination of the drugs thwarts the resistance pathways that arise against them singly.

Building the basis for new clinical trials

Moon shot preclinical work in prostate cancer cell lines and mouse models of cancer developed from human tumors focuses on identifying new combination therapy approaches for metastatic castrate- resistant cancer.

This research includes exploring the potential combination of androgen- targeting agents with drugs that hinder DNA damage repair to more efficiently destroy cancer cells.

Melanoma Moon Shot

Developing personalized treatment approaches through all stages of the disease is a central project, based on improved prognostic and predictive models that combine clinical, pathological, molecular and immunological factors. A series of clinical trials are underway based on this work.

Moon shot investigators have launched the first clinical trial to compare pre- surgical treatment with a targeted therapy combination to surgery alone for stage III melanoma. They are combining dabrafenib and trametinib, approved now for metastatic melanoma patients with BRAF mutations, as pre-surgical treatment to prevent recurrence after surgery for stage III disease.

Additional clinical trials pair targeted therapy with immune checkpoint blockade drugs that unleash an immune system attack on tumors.

Prevention by protection from ultraviolet rays

While they explore new ways to treat advanced melanoma, investigators are working to prevent damaging exposure to ultraviolet rays throughout childhood – from preschool through adolescence.

Researchers are developing an evidence- based sun protection program for preschoolers and promoting school-based efforts from kindergarten through high school. They are following up on successful efforts to limit tanning bed exposure by minors.

Moon shot surgeons, scientists, oncologists, behavioral scientists and governmental relations experts came together on behalf of a state ban on tanning bed use by minors that took effect in September 2013. They provided information on melanoma, its connection to UV light exposure and the impact of indoor tanning on melanoma risk, working with a broad coalition of groups supporting the ban.

Texas became the fifth state to pass a law banning the use of tanning beds by those under the age of 18. Eleven states have enacted similar laws, and the momentum continues to build.

Acute Myeloid Leukemia/Myelodysplastic Syndromes moon shot

This moon shot addresses resistance to hypomethylating agents, an important class of drugs used to treat these diseases. Their research has led to two clinical trials. One is the first conducted in leukemia of a rising type of cancer immunotherapy called immune checkpoint blockade.

Investigators implicated several immune checkpoint molecules, including PD-1, which shut down immune response, in the development of MDS resistance. In melanoma and other solid tumors, these checkpoints have been successfully targeted by antibodies, unleashing the immune system to attack cancer.

The team also identified the toll-like receptor 2 protein (TLR2) as a potential target and connected with an Irish biotech company to test an antibody to TLR2 in the second clinical trial.

Intensive research continues to identify other sources of resistance for MDS and AML employing analyses of DNA, RNA and protein activity.

Attacking with cellular immune therapies

A new project this year explores cellular immune therapy approaches to treating AML and MDS. Blood stem cell transplants can cure both diseases, and the key to eradication is the transplanted immune system’s action against leukemia. This team seeks first to improve the crucial graft-vs.-tumor response in blood stem cell transplantation.

The ultimate goal is to replace transplantation with treatment by engineered immune T cells and natural killer cells primed to find and kill cancer cells, such as those used in the CLL clinical trials. Technologies developed at MD Anderson by project leaders that can be readily translated into human clinical trials form the basis for this approach.

Game-changing technological advances support moon shots ‘Rocket science’ -- seeking wisdom via APOLLO

A central theme of the Moon Shots Program is to learn as much as we can from every single patient,” says Andy Futreal, Ph.D., professor of Genomic Medicine and the program’s co-leader with Draetta. “We need to think longitudinally — how patients’ conditions, treatments and tumors change over time — and be smarter about how we collect and use that information. To do this, we need to build an engine to learn.”

Futreal leads APOLLO, short for Adaptive Patient-Oriented and Longitudinal Learning and Optimization. It was piloted in Leukemia this year and is expanding to the lung and melanoma moon shots in 2014- 15.

APOLLO creates a more cohesive system for standardizing long-term collection of patients’ medical information, high-quality tissue and blood samples, and genomic and molecular analyses of those samples.

By seamlessly blending patient data, the latest research insights and best practices in clinical care, and analyzing it over time, APOLLO will help researchers improve patient care by addressing factors that determine treatment response, resistance, toxicity and patient survival.

Increasing the quality of information, then storing, accessing and analyzing it to apply to patients is something “every cancer research institution on the planet is struggling with right now,” Futreal said..”