Breast cancer remains the second most common cancer for American women. While treatment advances are being made, more research is needed. Current treatments don’t work for every woman.
 
Now, breast cancer researcher Svasti Haricharan, PhD, assistant professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), has been awarded more than half a million dollars in combined grants from Susan G. Komen® and the National Institutes of Health (NIH). 

This funding will advance Haricharan’s breast cancer research—including developing a diagnostic test that could guide therapeutic options—and allow her to apply lessons from breast cancer to additional cancers. 

Susan G. Komen grant

The majority of women diagnosed with breast cancer have the estrogen-positive (ER-positive) form, meaning the tumor grows in response to estrogen. Hormone therapies (anti-estrogen drugs) that block estrogen—and thus stop the tumor from growing—are available. However, this treatment doesn’t work for 40 percent of women with ER-positive breast cancer. 

“Currently, doctors are unable to predict which ER-positive patients will respond to treatment—so an estrogen-blocking medicine is given, and a ‘wait and see’ approach is taken to see if the treatment will work,” says Haricharan. “However, if a woman doesn’t respond to treatment, during this time the tumor is instead still growing and may metastasize—when it becomes deadlier and even harder to treat. Knowing upfront if an individual will respond to treatment allows doctors to skip a treatment that won’t work and move immediately to prescribing a medicine that may be effective.” 

Haricharan’s previous work found that about one-third of women with ER-positive breast cancer who were treatment resistant had a mutation in DNA damage-repair genes—providing a potential biomarker that could predict who would respond to treatment. 

Luckily, an FDA-approved test that detects defects in DNA damage repair is currently available for colorectal cancer patients. The grant from Susan G. Komen enables Haricharan to evaluate whether this same test can be used to predict response to anti-estrogen drugs in ER-positive breast cancer patients. 

Additionally, research from Haricharan’s previous lab identified a medicine that is FDA approved for advanced or metastatic breast cancer patients and holds potential as a frontline breast cancer treatment (the first treatment prescribed by a doctor). The grant will allow her to bring these pieces of the puzzle together—developing a predictive test and evaluating a potential alternative treatment. 

“Because an FDA-approved test is already on the market, development of a breast cancer test to predict response to hormone therapy may be accelerated. I’d estimate my work could enable a commercially available test in less than five years—though of course a real-world assessment will be needed to obtain doctor and insurance-company approval,” says Haricharan. “Pairing a new test that can guide therapeutic options with a potential treatment would be an important advance for ER- positive breast cancer. I want to express my greatest thanks to Susan G. Komen for funding this important work.” 

NIH grant

Haricharan was also awarded a K22 grant from the NIH, which helps early-career scientists transition to independent research careers. This grant will allow her to apply insights from her breast cancer research to additional cancers. 

Studies have indicated there are links between the growth of colorectal and bladder tumors and estrogen response. While women are less frequently diagnosed with bladder cancer, they tend to have a greater risk of dying from the disease. In contrast, estrogen may have a protective effect on the development of colorectal cancers. 

The NIH grant will enable Haricharan to work to better understand the role DNA damage-repair mutations may play in response to standard-of-care treatment for ER-positive breast, colorectal and bladder cancers. Once this role has been established, the grant will help fund a search for effective targeted treatments.

“Both bladder and colorectal cancers are often caught at a late stage, when the cancer is harder to treat,” says Haricharan. “I hope that this research will ultimately yield tests that can predict response to treatment and guide treatment options for these deadly cancers.” 

Link to the NIH grant: A pan-cancer role for MUTL loss in inducing treatment resistance 

More information about the Susan G. Komen grant: Susan G. Komen Announces $26 Million Investment in New Research to Find Solutions for Aggressive and Metastatic Breast Cancers, and to Help Communities Most at Risk
 

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It’s no surprise that our blood is important. The cargo it transports—nutrients, infection-fighting cells, clotting factors, waste and more—keeps our body healthy and running smoothly. So when blood cells don’t form properly, serious cancers can occur. 

Scientists divide blood cancers into three broad categories—leukemia, lymphoma and myeloma—based on the cell type affected. Leukemias disrupt white blood cell production; lymphomas affect the lymphatic system, which removes extra fluid from the body; and myelomas affect plasma cells, which produce intruder-fighting antibodies. There are many subsets within each category.

In honor of Blood Cancer Awareness Month, we spoke with Sanford Burnham Prebys Medical Discovery Institute scientist Ani Deshpande, PhD, to learn more about the blood cancer he studies: acute myeloid leukemia (AML). Of the 60,000 American children and adults diagnosed with leukemias each year, nearly 30 percent will have AML. 

• Most patients receive the same treatment used nearly five decades ago. Drug developers have created medicines for AML patients who have certain changes in their DNA, called mutations. But the majority of AML patients receive the treatments used in the ’70s: chemotherapy, radiation and possibly a bone marrow transplant. This isn’t last-decade science; it’s last-century science.
• It’s deadly. The five-year survival rate for adults with AML—the number of people who are alive five years after diagnosis—is only 24 percent, according to the American Cancer Society. New medicines and treatment approaches are urgently needed. 
• Sequencing is making strides. Now, scientists can sequence patients’ genomes to learn the underlying mutation driving their cancer. This technology has advanced our understanding to the point that about 60 to 70 percent of the time, their doctor knows the mutation involved. Our new problem is that we don’t have effective medicines that target most of these mutations. 
• Speaking of sequencing. Because of DNA sequencing, we also know that a large fraction of the mutations in AML are epigenetic changes—alterations that affect which genes turn on but don’t change the DNA itself.

To better understand how epigenetic changes work, imagine a cookbook. If recipes are DNA,               then epigenetic changes are bookmarks. These bookmarks signal whether the recipe should be made or not, without altering the underlying text of the recipe.

Our laboratory is studying the epigenetic changes that drive AML. Our hope is that once we identify these changes, we can create drugs that restore the epigenome to its normal state. 

• There is hope. After nearly 50 years of little progress, four new drugs have been approved for AML over the last 18 months. And there are currently more than 330 clinical trials enrolling patients in the U.S., so more treatments may soon follow. 

Resources:

• American Society of Hematology: Blood basics 
• American Cancer Society: What is Acute Myeloid Leukemia? 

Interested in keeping up with Sanford Burnham Prebys’ latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.
 

The Cancer Immunology and Tumor Microenvironment Symposium held at Sanford Burnham Prebys Medical Discovery Institute (SPB) on March 8, 2018 attracted a full house of international attendees. Its success likely stems from the impressive roster of speakers invited by Carl Ware, PhD, director of the Infectious and Inflammatory Diseases Center and Linda Bradley, PhD, also a professor in that program. The presenters included many thought leaders in the field from such prestigious institutions as University of Pittsburgh, University of Ontario Fred Hutchinson Cancer Research Center, the Mayo Clinic, Moores Cancer Center at UC San Diego and University of Washington School of Medicine.

Today, immunotherapy is one of the most exciting areas of new discoveries and treatments for many types of cancer. Although huge strides have been made—some patients experience complete remission—more breakthroughs are needed. Some patients do not respond at all, some relapse and others experience undesirable, often life-threatening side effects. And some cancers, such a pancreatic, brain, breast and prostate, have shown very limited benefit.

“This symposium brings experts in the fields of cancer and immunology together to promote scientific exchange and collaboration,” says Ware. “It’s meetings like this that will help us accelerate the understanding and development of new immune system-based therapies for cancer patients.”

Throughout our lives, our bodies must maintain a continual balance of cell growth and cell death—especially to eliminate unwanted cells, like cancer cells.  This balance is coordinated by some proteins that promote cell death and others that support cell survival.

Francesca Marassi, PhD, professor at SBP’s NCI-designated Cancer Center, studies one of the proteins involved in this balance, Bcl-xL. Bcl-xL is a protein that promotes survival by binding to and sequestering proteins that promote cell death. This function makes Bcl-xL an intriguing focus for drug development.

“Studying Bcl-xL is important because this protein is expressed at abnormally high levels in many types of cancer,” Marassi explains. “Blocking its function causes cancer cells to die, making Bcl-xL an important cancer drug target. Understanding its structure is key to designing effective drugs to block its activity.”

Current understanding of Bcl-xL’s structure describes a protein with three regions – a core that interacts with proteins involved in cell death, a flexible region lacking defined structure (IDR) with an unknown function, and a membrane-anchoring region that attaches the protein to specific sites within the cell. Marassi’s group is the first to be able to produce complete Bcl-xL molecules containing all three domains, an essential advance in the field previously described in the Journal of Molecular Biology.

“Most studies have used shortened versions of Bcl-xL that only contain the core region, but our method creates a molecule that better resembles the actual form in our cells,” Marassi says. “Using our version allows us to ask questions about how the protein’s different regions interact with each other. This will help us understand how the entire protein works together to block cell death, and may provide new sites to target in drug discovery.”

In collaboration with Richard Kriwacki, PhD at St. Jude Children’s Research Hospital, Marassi’s proteins were used to show that Bcl-xL’s IDR controls the core’s ability to interact with its binding partners. By combining their areas of expertise, the two labs demonstrated that changes to the chemistry of the IDR altered the structure of the core region of the Bcl-xL protein. When they altered the IDR to match changes that occur in normal cells at the start of the cell death process, the core region changed to a closed structure. This change hid Bcl-xL’s binding site, preventing it from blocking the activity of cell death-promoting proteins.

“We are next interested in determining if Bcl-xL’s method of self-regulation also occurs when it is embedded in a cell membrane, where Bcl-xL would be found in a normal cell,” Marassi says. “If we can show that the same interaction between the IDR and core occurs at the membrane, it is likely that this control occurs naturally in cells. This opens up the possibility that drugs to block Bcl-xL’s anti-death function could target the more accessible IDR region, rather than the protected core region.”

Pancreatic cancer is relatively rare, but when it occurs it tends to be deadly—just 5 percent of patients survive five years or more past diagnosis.  A new study co-authored by Jorge Moscat, PhD, and Maria Diaz-Meco PhD, professors at SBP’s NCI-designated Cancer Center, looks at ways to detect and stop precursors of pancreatic cancer—premalignant lesions known as intraepithelial neoplasia 1 (PanIN1)—before they become cancer. PanIN1 lesions are relatively common, affecting 16 percent of healthy adults and 60 percent of people with chronic pancreatitis, or inflammation of the pancreas. 

Yet only 1 percent of PanIN1 lesions will lead to the most lethal form of pancreatic cancer—the challenge is predicting which people have the particularly insidious lesions.  There are several risk factors—having first-degree relatives with pancreatic cancer, chronic pancreatitis, obesity, diabetes, tobacco smoking and alcohol consumption, for example—but it’s not known how these risk factors trigger the conversion of a PanIN1 lesion to cancer.

The study, published in Cancer Cell and led by Michael Karin, PhD, distinguished professor of Pharmacology and Pathology at UC San Diego School of Medicine, discovered that in human cells and mice, interference with autophagy, a cell process that gets rid of faulty proteins and cell trash, worsens the damage to pancreatic cells that produce digestive enzymes. The disruption leads to the accumulation of a protein called p62/SQSTM1, which is typically elevated in chronic pancreatitis and PanIN lesions.

Moscat, an authority on p62 and cancer, explains that impaired autophagy can lead to a build up of p62/SQSTM1, helping precursor lesions advance to full-blown pancreatic cancer through specific molecular steps. First, p62 stimulates a protein in the cell nucleus called NRF2. Then NRF2 stimulates a protein MDM2. Elevated MDM2 converts cells that have certain cancer-causing gene mutations into rapidly multiplying pancreatic ducts cells. These duct cells in turn give rise to malignant pancreatic cancer.

According to Diaz-Meco, when the researchers used an investigational drug that targets MDMs, they were able to prevent cancer progression in mice, and even restore normal pancreatic cell identity.

These findings suggest that treatment of individuals who are at high risk of pancreatic cancer may benefit from treatment with MDM2 inhibitors,” explains Diaz-Meco. “MDM2 inhibitors may prevent PanIN lesions from becoming cancer, reducing the toll of this currently incurable malignancy.”

The story is based on a UCSD Health Sciences report.