cell death Archives - Sanford Burnham Prebys

Tag: cell death

Institute News

Two Sanford Burnham Prebys scientists selected for American Cancer Society postdoctoral fellowships

AuthorGreg Calhoun
Date

October 18, 2024

combined photos of Alicia Llorente Lope and Ambroise Manteau
Alicia Llorente Lope, PhD, is a postdoctoral associate in the lab of Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. Ambroise Manceau, PhD, is a postdoctoral associate in the lab of Cosimo Commisso, PhD, interim director and deputy director of the institute’s NCI-Designated Cancer Center.

Funds will support Alicia Llorente Lope and Ambroise Manceau who study breast and pancreatic cancer

Alicia Llorente Lope, PhD, and Ambroise Manceau, PhD, were awarded 2024 Postdoctoral Fellowships from the American Cancer Society (ACS). These prestigious awards provide more than $65,000 per year for up to three years to support early career scientists studying cancer.

“I was so excited when I heard the news,” said Llorente. “It is a privilege to have this award, and it feels very validating to know that someone saw enough potential in my research to deem it worthy of funding.”

Tackling treatment-resistant breast cancer

Llorente joined the lab of Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, nearly three years ago after beginning her breast cancer research career as a doctoral student.

“I was first interested in breast cancer because my grandmother died of the disease, and I wanted to contribute to finding new therapeutic opportunities for cancer patients,” said Llorente. Llorente’s ACS-funded research project focuses on HER2-positive (HER2+) breast cancer.

Roughly one in five breast cancer tumors have elevated levels of the HER2 protein. While these tumors tend to grow quickly, drugs targeting the HER2 protein are usually effective at first. However, HER2+ tumors often are able to adapt and develop resistance to these drugs over time, leaving patients with few if any remaining treatments options.

Llorente has found evidence that a form of the protein phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) plays a role in breast cancer tumors becoming resistant to HER2 drugs.

Brooke Emerling

Brooke Emerling, PhD

“We’ve revealed a strong connection between elevated levels of PI5P4K gamma and reduced survival rates in patients with HER2+ breast cancer,” explained Llorente. “I plan to explore whether targeting both HER2 and PI5P4K gamma in breast cancer cells may provide a path to overcoming treatment resistance.” Llorente also will study the functions of PI5P4K gamma in breast cancer cells to see why these cells cease to respond to HER2-targeting drugs.

“I am incredibly proud of Alicia for spearheading this groundbreaking project targeting the lipid kinase PI5P4K gamma,” said Emerling. “Her insightful analysis of breast cancer datasets, which uncovered a correlation between elevated expression of PI5P4K gamma and worse outcomes in HER2+ patients, has set the stage for vital research aimed at overcoming the significant challenge of resistance to targeted therapies in HER2+ tumors.”

Cosimo Commisso headshot

Cosimo Commisso, PhD

Powering down pancreatic cancer

Manceau is in the second year of his postdoctoral training in the lab of Cosimo Commisso, PhD, interim director and deputy director of the institute’s NCI-Designated Cancer Center. During his doctoral program, Manceau studied how abnormal cells die in a programmed series of steps called apoptosis, a process known to go awry in cancer and neurodegenerative diseases.

“It began as a basic science project about the molecular processes around cell death, and over time it led to possible therapeutic implications,” said Manceau. “I learned that I like to study fundamental biology and then try to find an application for it, and I saw in the Commisso lab an opportunity to do just that in pancreatic cancer.”

Manceau’s fellowship project focuses on pancreatic ductal adenocarcinoma (PDAC) — the most common form of pancreatic cancer with only a 13% five-year survival rate — and its ravenous pursuit of energy. Because of PDAC cells’ constant need for fuel to sustain their rampant growth, they adapt by reshaping the surface of their cells to snatch extra nutrients from the jelly-like substance between cells.

Commisso and others have shown that cutting off the extra power supplied by this process — known as macropinocytosis — reduces tumor growth. Manceau has studied the contents taken by contorted pancreatic cell surfaces in pockets called macropinosomes. By analyzing every single protein in this scooped goop, he found that calcium transporter proteins present in macropinosomes also are required for macropinocytosis.

“During the fellowship, I will work to understand how these transporter proteins affect macropinocytosis,” said Manceau. “These proteins have never been targeted before in pancreatic cancer, so our long-term goal is to use this strategy to cut the nutrient supply to tumors and see if we can inhibit tumor growth.”

“By disrupting the cancer cells’ ability to feed themselves through macropinocytosis, we can potentially starve tumors and inhibit their growth,” added Commisso. “Ambroise’s research aims to target key proteins involved in this process, opening up new possibilities for treatments that could significantly improve outcomes for patients battling pancreatic cancer.”

Institute News

New study honors SBP scientist Marcia Dawson

AuthorSusan Gammon
Date

June 11, 2018

Marcia Dawson post

Professor Marcia Dawson was a fixture at Sanford Burnham Prebys for more than 25 years. The Stanford-educated biochemist was particularly interested in synthesizing compounds that induce apoptosis (programmed cell death) in tumors. Dawson passed away in 2016, but her work has continued.

Recently, researchers investigated several variations of a compound produced in the Dawson laboratory, called DIM-Ph-4-CF3. This molecule is designed to modulate a nuclear receptor protein called NR4A1. In this paper, published in the journal Oncotarget, the multi-lab team investigated whether oxidized versions of the compound could be even more potent against cancer.

“We tested a number of analogs, and I think the most interesting thing is that the oxidation products were more potent than their parent form,” said Marisa Sanchez, a PhD candidate in the lab of Dieter Wolf, PhD, and the first author on the paper. “This potency was exhibited by a significant decrease of cell viability in multiple cancer lines. They kill cancer very well.”

The NR4A1 receptor is usually found in the cell’s nucleus and cytoplasm. When modulated by the DIM-Ph-4-CF3 products, the cytoplasmic fraction appears to trigger the unfolded protein response, a cellular stress mechanism that often leads to apoptosis. The anti-cancer molecules showed particularly strong activity in prostate cancer and exhibited no obvious side effects.

As work continues on these molecules, they could potentially be used to augment the cancer-killing impact of chemotherapy or other treatments. Over time, cancer cells can evolve the ability to resist apoptosis, and this approach might work synergistically with existing therapies to overcome that resistance.

“They target those pathways in a different way to induce cell death,” says Sanchez. “It might be harder for cancers to develop resistance.”

Still, it’s quite early in the discovery process, and much more work needs to be done. Sanchez feels that further investigation could confirm the mechanism of action and perhaps make the molecule more specific.

In addition to being a rewarding effort to develop and test new anticancer molecules, this was a labor of love for the research team, several of whom had worked with Dawson for decades.

“We finished this in Marcia’s memory,” says Sanchez. “We really wanted to honor her.”

Institute News

How RNA splicing can trigger cancer

AuthorSusan Gammon
Date

September 21, 2017

DNA and RNA helix

Cancer, which is one of the leading causes of death worldwide, arises from the disruption of essential mechanisms of the normal cell life cycle, such as replication control, DNA repair and cell death. Thanks to the advances in genome sequencing techniques, biomedical researchers have been able to identify many of the genetic alterations that occur in patients that are common among and between tumor types. But until recently, only mutations in DNA were thought to cause cancer. In a new study published in the journal Cell Reports, researchers show that alterations in a process known as alternative splicing may also trigger the disease.

Although DNA is the instruction manual for cell growth, maturation, division, and even death, it’s proteins that actually carry out the work. The production of proteins is a highly regulated and complex mechanism: cellular machinery reads the DNA fragment that makes up a gene, transcribes it into RNA and, from the RNA, makes proteins. However, each gene can lead to several RNA molecules through alternative splicing, an essential mechanism for multiple biological processes that can be altered in disease conditions.

Using data for more than 4,000 cancer patients from The Cancer Genome Atlas (TCGA project), an international team of scientists that included Adam Godzik, PhD, professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), has analyzed the changes in alternative splicing that occur in each tumor patient and studied how these changes could impact the function of genes. The results of the study show that alternative splicing changes lead to a general loss of functional protein domains, and particularly those domains related to functions that are also affected by genetic mutations in cancer patients.

From previous work, the research team learned that tumor type and stage can be predicted by observing alterations in alternative splicing. With this new study, the team discovered that changes in alternative splicing that occur in cancer impact protein functions in a way that is similar to that previously described for genetic mutations.

All of these alterations in protein functions would cause changes in cells morphology and function, giving them the characteristics of tumor cells, such as a high proliferative potential or the ability to avoid programmed cell death.

According to Godzik, “These changes potentially have oncogenic power in cells, which means, the ability to turn a healthy cell into a cancer cell.” A novel aspect of the study is that these changes tend to occur in genes other than those often mutated in cancer, and in patients with a low number of mutated genes.

“Changes in alternative splicing provide cancer with new ways in which it can escape fine cellular regulation. Therefore, the study of alternative splicing opens new doors in the research to cure cancer and may provide new alternatives to the treatment of this disease.

Institute News

Leukemia research breakthrough: a new way to trigger cancer cell suicide

AuthorJessica Moore
Date

May 18, 2016

Header image

Better therapies for acute myeloid leukemia (AML), a fast-growing cancer of the bone marrow, are urgently needed. Nearly 15,000 people in the United States are diagnosed with AML each year, and it’s the most common acute leukemia in adults. The cause of the disease is unknown, and it is usually fatal within the first five years. Continue reading “Leukemia research breakthrough: a new way to trigger cancer cell suicide”

Institute News

Researchers reawaken sleeping HIV in patient cells to eliminate the virus

Authorsgammon
Date

September 9, 2015

Header image

Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new class of drugs that may be used to purge pockets of dormant HIV from a patient’s body, eliminating the virus once and for all. Fortuitously, these agents are already being explored in clinical trials for treating cancer, which could speed up the route to approval for treating HIV.

Antiretroviral therapies have made it possible for people to live with AIDS for decades. However, small reservoirs of a patient’s cells hide the virus. That is, HIV’s genes live in the cells, but its genetic code is never read to make protein, and so the virus goes undetected by the immune system.

“If you take people off the antiretroviral therapies, some of these dormant cells reawaken to make more virus,” said lead author Lars Pache, PhD, a postdoctoral fellow in the lab of Sumit Chanda, PhD, director of the Immunity and Pathogenesis Program at SBP. “The key for a cure for HIV is to purge these cells that have dormant HIV.”

Reactivating latent HIV-infected cells so that they can be killed off once and for all is called ‘shock and kill.’ The approach has remained elusive so far, because drugs that reawaken the virus could also trigger massive immune system activation, which itself could be deadly, Chanda said.

The new study, published September 9 in the journal Cell Host & Microbe, “uses a class of drug called Smac mimetics to tap into a cell pathway that can be used to wake up the virus but, based on clinical studies and our data, doesn’t appear to activate the immune system,” Chanda added.

The study started with a broad search of genes within the host cells that help keep the virus silent. Chanda’s group identified 651 genes. They then created batches of cells in which each one of those genes was silenced, and they measured how much HIV the cells produced after they were exposed to the virus.

The scientists whittled the list of candidate genes down to 139, to 24, and then 12 using increasingly stringent criteria. The absence of one gene in particular, BIRC2, boosted the activity of HIV. Even better, Smac mimetics—already proven safe in early-stage clinical trials for cancer—works by inhibiting BIRC2 and related molecules.

“These experiments led us to develop a strategy of using Smac mimetics to reawaken dormant HIV so that we could then kill it with anti-viral therapy,” said Chanda.

Chanda’s colleague at SBP, Nicholas Cosford, PhD, professor in the Cell Death and Survival Networks Program, had recently described a potent BIRC2 inhibitor, SBI-0637142. “This drug is about 10-100 times more potent than the small molecules currently in clinic development, making it a promising candidate to tackle HIV latency,” says Chanda.

Part of the reason that HIV’s genes stay hidden in its host is that they cover themselves with tightly wound DNA. A class of drugs called histone deacetylase inhibitors, which unfurls the DNA, is used to treat a variety of conditions. Although most of these inhibitors haven’t worked well on their own to reactivate latent HIV, they might work well with Smac mimetics including SBI-0637142, Chanda’s group reasoned.

The key question was whether they could reactivate the virus in cells from HIV-infected patients undergoing antiretroviral therapy. They combined SBI-0637142 with a histone deacetylase inhibitor (panobinostat) and saw signs that the virus had reawakened without triggering immune cell death.

“We anticipated that we would see a synergy because the drugs work along parallel pathways. What we didn’t expect was the level of activation—the potency and efficacy with which we were able to reverse latency in patient samples,” Chanda said.

They saw similar results in patient cells treated with a combination of LCL161—a Smac mimetic that is already in phase 1 and 2 trials for treating cancer—and panobinostat. “This is a one-two punch for HIV,” said Chanda, adding that ultimately, a cocktail of drugs will be necessary to cure HIV.

The scientists hope to partner with a pharmaceutical company to develop these molecules for testing in animal models of HIV and then move them into the clinic if they meet the safety and efficacy criteria.

In addition to SBP, the study consortium included the University of Utah School of Medicine, The Salk Institute for Biological Studies, the Perelman School of Medicine at the University of Pennsylvania, the Icahn School of Medicine at Mount Sinai, the Paul-Ehrlich-Insitut, and the German Center for Infection Research.

This post was written by Kelly Chi, a freelance science writer.