Research Targeting Prostate Cancer Gets Almost $4 Million Support from CIRM

Prostate cancer

A program hoping to supercharge a patient’s own immune system cells to attack and kill a treatment resistant form of prostate cancer was today awarded $3.99 million by the governing Board of the California Institute for Regenerative Medicine (CIRM)

In the U.S., prostate cancer is the second most common cause of cancer deaths in men.  An estimated 170,000 new cases are diagnosed each year and over 29,000 deaths are estimated in 2018.  Early stage prostate cancer is usually managed by surgery, radiation and/or hormone therapy. However, for men diagnosed with castrate-resistant metastatic prostate cancer (CRPC) these treatments often fail to work and the disease eventually proves fatal.

Poseida Therapeutics will be funded by CIRM to develop genetically engineered chimeric antigen receptor T cells (CAR-T) to treat metastatic CRPC. In cancer, there is a breakdown in the natural ability of immune T-cells to survey the body and recognize, bind to and kill cancerous cells. Poseida is engineering T cells and T memory stem cells to express a chimeric antigen receptor that arms these cells to more efficiently target, bind to and destroy the cancer cell. Millions of these cells are then grown in the laboratory and then re-infused into the patient. The CAR-T memory stem cells have the potential to persist long-term and kill residual cancer calls.

“This is a promising approach to an incurable disease where patients have few options,” says Maria T. Millan, M.D., President and CEO of CIRM. “The use of chimeric antigen receptor engineered T cells has led to impressive results in blood malignancies and a natural extension of this promising approach is to tackle currently untreatable solid malignancies, such as castrate resistant metastatic prostate cancer. CIRM is pleased to partner on this program and to add it to its portfolio that involves CAR T memory stem cells.”

Poseida Therapeutics plans to use the funding to complete the late-stage testing needed to apply to the Food and Drug Administration for the go-ahead to start a clinical trial in people.

Quest Awards

The CIRM Board also voted to approve investing $10 million for eight projects under its Discovery Quest Program. The Quest program promotes the discovery of promising new stem cell-based technologies that will be ready to move to the next level, the translational category, within two years, with an ultimate goal of improving patient care.

Among those approved for funding are:

  • Eric Adler at UC San Diego is using genetically modified blood stem cells to treat Danon Disease, a rare and fatal condition that affects the heart
  • Li Gan at the Gladstone Institutes will use induced pluripotent stem cells to develop a therapy for a familial form of dementia
  • Saul Priceman at City of Hope will use CAR-T therapy to develop a treatment for recurrent ovarian cancer

Because the amount of funding for the recommended applications exceeded the money set aside, the Application Subcommittee voted to approve partial funding for two projects, DISC2-11192 and DISC2-11109 and to recommend, at the next full Board meeting in October, that the projects get the remainder of the funds needed to complete their research.

The successful applications are:

 

APPLICATION

 

TITLE

 

INSTITUTION

CIRM COMMITTED FUNDING
DISC2-11131 Genetically Modified Hematopoietic Stem Cells for the

Treatment of Danon Disease

 

 

U.C San Diego

 

$1,393,200

 

DISC2-11157 Preclinical Development of An HSC-Engineered Off-

The-Shelf iNKT Cell Therapy for Cancer

 

 

U.C. Los Angeles

 

$1,404,000

DISC2-11036 Non-viral reprogramming of the endogenous TCRα

locus to direct stem memory T cells against shared

neoantigens in malignant gliomas

 

 

U.C. San Francisco

 

$900,000

DISC2-11175 Therapeutic immune tolerant human islet-like

organoids (HILOs) for Type 1 Diabetes

 

 

Salk Institute

 

$1,637,209

DISC2-11107 Chimeric Antigen Receptor-Engineered Stem/Memory

T Cells for the Treatment of Recurrent Ovarian Cancer

 

 

City of Hope

 

$1,381,104

DISC2-11165 Develop iPSC-derived microglia to treat progranulin-

deficient Frontotemporal Dementia

 

 

Gladstone Institutes

 

$1,553,923

DISC2-11192 Mesenchymal stem cell extracellular vesicles as

therapy for pulmonary fibrosis

 

 

U.C. San Diego

 

$865,282

DISC2-11109 Regenerative Thymic Tissues as Curative Cell

Therapy for Patients with 22q11 Deletion Syndrome

 

 

Stanford University

 

$865,282

 

 

Stem cell study holds out promise for kidney disease

Kidney failure

Image via youtube.com

Kidney failure is the Rodney Dangerfield of diseases, it really doesn’t get the respect it deserves. An estimated 660,000 Americans suffer from kidney failure and around 47,000 people die from it every year. That’s more than die from breast or prostate cancer. But now a new study has identified a promising stem cell candidate that could help in finding a way to help repair damaged kidneys.

Kidneys are the body’s waste disposal system, filtering our blood and cleaning out all the waste products. Our kidneys have a limited ability to help repair themselves but if someone suffers from chronic kidney disease then their kidneys are slowly overwhelmed and that leads to end stage renal disease. At that point the patient’s options are limited to dialysis or an organ transplant.

Survivors hold out hope

Italian researchers had identified some cells in the kidneys that showed a regenerative ability. These cells, which were characterized by the expression of a molecule called CD133, were able to survive injury and create different types of kidney cells.

Researchers at the University of Torino in Italy decided to take these findings further and explore precisely how CD133 worked and if they could take advantage of that and use it to help repair damaged kidneys.

In their findings, published in the journal Stem Cells Translational Medicine, the researchers began by working with a chemotherapy drug called cisplatin, which is used against a broad range of cancers but is also known to cause damage to kidneys in around one third of all patients. The team found that CD133 was an important factor in helping those damaged kidneys recover. They also found that CD133 prevents aging of kidney progenitor cells, the kind of cell needed to help create new cells to repair the kidneys in future.

Hope for further research

The finding opens up a number of possible lines of research, including exploring whether infusions of CD133 could help patients whose kidneys are no longer able to produce enough of the molecule to help repair damage.

In an interview in DD News, Dr. Anthony Atala, Director of the Wake Forest Institute for Regenerative Medicine – praised the research:

“This is an interesting and novel finding. Because the work identifies mechanisms potentially involved in the repair of tissue after injury, it suggests the possibility of new therapies for tissue repair and regeneration.”

CIRM is funding several projects targeting kidney disease including four clinical trials for kidney failure. These are all late-stage kidney failure problems so if the CD133 research lives up to its promise it might be able to help people at an earlier stage of disease.

New developments in prostate cancer from UCLA

Today we’re bringing you a research update from a CIRM-funded team at UCLA that’s dedicated to finding a cure for prostate cancer. The team is led by Dr. Owen Witte, the director of the UCLA Broad Stem Cell Research Center and a Howard Hughes Investigator. Dr. Witte is well known for his work in leukemia and epithelial cancer stem cells. His interests have also expanded into prostate cancer and identifying new therapeutic targets for the most aggressive types of prostate tumors.

His team’s latest efforts, which were published in Cancer Cell last week, have unearthed a possible target for late-stage neuroendocrine prostate cancer treatment. This is a particularly nasty form of prostate cancer that is resistant to standard cancer treatments and is the cause of approximately a quarter of prostate cancer related deaths.

Myc-ing prostate cells cancerous

To study how neuroendocrine prostate cancer (NEPC) develops into uncontrollable tumors, Witte and his team developed a novel human stem cell model. They knew that patients with NEPC had abnormally high levels of a protein called N-Myc in their tumors. Witte had a hunch that maybe N-Myc was the “bad guy” that was transforming normal human prostate cells into deadly, aggressive cancer cells. So the team went on an adventure to find some answers.

Normal prostate cells (left) and neuroendocrine prostate cancer cells (right). (UCLA news release)

Normal prostate cells (left) and neuroendocrine prostate cancer cells (right). (UCLA news release)

They took normal human prostate cells from healthy donors and added the MYCN gene which then produced large amounts of N-Myc protein. After receiving an N-Myc boost, the normal basal cells developed into aggressive tumor cells. When these transformed cells were transplanted into mice, they generated NEPC tumors.

Naturally, Witte didn’t stop there. He was interested in understanding what was going on at the cellular level to transform normal prostate cells into cancer. Witte explained in a UCLA press release:

“Identifying the cellular changes that happen in cancer cells is key to the development of drugs that inhibit those changes and thereby stop the progression of the disease.”

 

Finding drugs that target prostate cancer

Further experiments revealed that N-Myc was required for maintaining the deadly nature of the NEPC tumors. If N-Myc expression was disrupted, then the tumors in the mice actually shrank. After establishing N-Myc as a therapeutic target, they went on a hunt for drugs that could block its tumor amplifying activity.

They tested a drug that originally was designed to treat childhood brain cancers that also had an N-Myc related cause. The drug, CD532, acts on a protein called Aurora A kinase. The kinase physically interacts with N-Myc and is required to keep N-Myc stable and able to do its job. When mice with NEPC tumors were treated with CD532, the effects were dramatic – their tumors shrank by as much as 80%.

Witte believes that some of the cellular mechanisms behind the growth of different cancers are conserved. He explained,

Owen Witte and first author John Lee (UCLA).

Owen Witte and first author John Lee (UCLA).

“Kinase activity is known to be implicated in many types of cancers, including chronic myelogenous leukemia, which is no longer fatal for many people due to the success of Gleevec. I believe we can accomplish this same result for people with neuroendocrine prostate cancer.”

According to Witte, the next chapter in this story will be to find other drugs that can treat NEPC possibly by targeting N-Myc. Testing CD532 in clinical trials is also an option. Thus far, the drug has only been tested in preclinical experiments and hasn’t progressed into clinical trials for safety and efficacy testing in humans.


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Using baking ingredient to create “nano” bombs and destroy cancer stem cells

Nixon_30-0316a

“I am not a cook”. Richard Nixon and the baking ingredient that could help win the “war on cancer”

In 1971 President Richard Nixon declared a “war on cancer” and signed the National Cancer Act into law. Forty years later we’re still waging that war, and cancer is still one of the leading causes of death. But now researchers in Ohio have unveiled a new weapon; a nanobomb that targets cancer stem cells.

In treating invasive cancers the standard weapons are chemotherapy and radiation, but cancer stem cells are somehow able to evade these and lie dormant. Eventually they emerge from hiding and multiply and spread throughout the body, leading to a recurrence of the cancer.

So researchers at The Ohio State University Comprehensive Cancer Center turned to nanoparticles to try and target them. Nanoparticles for those of who aren’t up on the latest trendy science topics (something I plead guilty to) are particles between 1 and 100 nanometers in size. Just to put it in context, that’s about one billionth of a meter. In other words, very small indeed.

In the past when scientists tried to use nanoparticles to carry anti-cancer therapies such as therapeutic RNA to the tumor, the cancer cells simply enfolded the RNA nanoparticles in a kind of compartment called an endosome, which rendered them useless.

In a news release, principal investigator Xiaoming He said their new approach helps the nanoparticles escape from the endosomes and attack the cancer:

“We believe we’ve overcome this challenge by developing nanoparticles that include ammonium bicarbonate, a small molecule that vaporizes when exposing the nanoparticles to near-infrared laser light, causing the nanoparticle and endosome to burst, releasing the therapeutic RNA.”

In the study, published in Advanced Materials,   He and his team put micro-RNA miR-34a inside the nanoparticles. This is a molecule known to lower the levels of a  protein that cancer stem cells need for survival. When the ammonium bicarbonate was hit with the near-infrared laser it caused the endosomes to burst and released the miR-34a, killing the cancer cell.

When they tested this approach in a mouse model of human prostate cancer it significantly reduced the size of the tumors.

Because near-infrared lasers penetrate to about half an inch this method could be used for tumors near the skin surface, and for deeper ones would only require a minimally invasive surgery to deliver the necessary dose of light.

Ammonium bicarbonate, the ingredient used to help the nanoparticles swell up, is used by the food industry for some baked goods such as cookies and crackers. It’s a little odd to think that something used in such tasty treats could also be potentially deadly – think about that next time you are browsing the cookie aisle at the supermarket.

 

 

 

 

 

 

 

 

UCLA scientists find new targets for late-stage prostate cancer

Prostate cancer, which currently affects 3 million men in the United States, is no longer a death sentence if caught early. The five-year survival rate is very high (~98%) because of effective treatments like hormone therapy, chemotherapy, surgery, and radiation—and for many men with slow progressing tumors, the wait-and-watch approach offers an alternative to treatment.

However, for those patients who have more aggressive forms of prostate cancer, where the tumors spread to other organs and tissues, the five-year survival rate is much lower (~28%) and standard therapies only work temporarily until the tumors become resistant to them. Thus there is a need for finding new therapeutic targets that would lead to more effective and longer-lasting treatments.

Kinases are ABL to cause cancer

We recently wrote a blog about prostate cancer featuring the work of a pioneer in cancer research, Dr. Owen Witte from the UCLA Broad Stem Cell Research Center. Dr. Witte is well known for his work on understanding the biology of blood cancers (leukemias) and the role of cancer stem cells. One of his key discoveries was that the cancer-causing BCR-ABL gene produces an overactive protein kinase that causes chronic myelogenous leukemia (CML).

Protein kinases are enzymes that turn on important cell processes like growth, signaling, and metabolism, but they also can be involved in causing several different forms of cancer. This has made some kinases a prime target for developing cancer drugs that block their cancer-causing activity.

New targets for late-stage prostate cancer

Recently, Dr. Witte’s interests have turned to understanding and finding new treatments for aggressive prostate cancers. He has been on the hunt for new targets, and this week, Witte and his group published a CIRM-funded study in the journal PNAS showing that a specific set of kinases are involved in causing advanced stage prostate cancer that spreads to bones.

They selected a group of 125 kinases that are known to be active in aggressive forms of human cancers. From this pool, they found that 20 of these kinases caused metastasis, or the spreading of cancer cells from the starting tumor to different areas of the body, when activated in mouse prostate cancer cells that were injected into the tail veins of mice.

To narrow down the pool further, they activated each of the 20 kinases in human prostate cancer cells and injected these cells into the tails of mice. They found that five of the kinases caused the cancer cells to leave the tail and metastasize into the bones. When they compared the activity of these five kinases in the late-stage and early-stage prostate cancer cells as well as normal prostate cells, they only saw activity of these kinases in the late-stage cancer cells.

Microscopic view of a hip bone (left) and a magnified view of the bone showing the metastasized prostate cancer tumor (T), healthy bone marrow (M) and bone (B). Image courtesy of the UCLA Broad Stem Cell Research Center.

Microscopic view of a hip bone (left) and a magnified view of the bone showing the metastasized prostate cancer tumor (T), healthy bone marrow (M) and bone (B). Image courtesy of the UCLA Broad Stem Cell Research Center.

New treatment option?

Witte and his colleagues concluded that these five kinases can cause prostate tumor cells to spread and metastasize into bones, and that targeting kinase activity could be a new therapeutic strategy for late-stage prostate cancer patients that have exhausted normal treatment options.

In a UCLA press release, Claire Faltermeier, the study’s first author and a medical and doctoral student in Witte’s lab commented:

Our findings show that non-mutated protein kinases can drive prostate cancer bone metastasis. Now we can investigate if therapeutic targeting of these kinases can block or inhibit the growth of prostate cancer bone metastasis.

 

Dr. Witte followed up by mentioning the promise of targeting kinase activity for late-stage prostate cancer:

Cancer-causing kinase activity has been successfully targeted and inhibited before. As a result, chronic myelogenous leukemia is no longer fatal for many people. I believe we can accomplish this same result with advanced stages of prostate cancer with a fundamental understanding of the cellular nature of the disease.

UCLA scientists Owen Witte and

UCLA scientists Owen Witte and Claire Faltermeier


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Stem cells and prostate cancer are more similar than we thought

Prostate cancer is a scary word for men, no matter how macho or healthy they are. These days however, prostate cancer is no longer a death sentence for them. In fact, many men survive this disease if diagnosed early. However, for those unlucky ones who have more advanced stages of prostate cancer (where the tumor has metastasized and spread to other organs), the typical treatments used to fight the tumors don’t work effectively because advanced tumors become resistant to these therapies.

To help those afflicted with late stage prostate cancer, scientists are trying to understand the nature of prostate cancer cells and what makes them so “deadly”. By understanding the biology behind these tumor cells, they hope to develop better therapies to treat the late-stage forms of this disease.

UCLA scientists Bryan Smith and Owen Witte. (Image credit: UCLA Broad Stem Cell Research Center)

UCLA scientists Bryan Smith and Owen Witte. (Image credit: UCLA Broad Stem Cell Research Center)

But don’t worry, help is already on its way. Two groups from the University of California, Los Angeles and the University of California, Santa Cruz published a breakthrough discovery yesterday on the similarity between prostate cancer cells and prostate stem cells. The study was published in the journal PNAS and was led by senior author and director of the UCLA Broad Stem Cell Research Center, Dr. Owen Witte.

Using bioinformatics, Witte and his team compared the gene expression profiles of late-stage, metastatic prostate cancer cells sourced from tumor biopsies of living patients to healthy cell types in the male prostate. Epithelial cells are one of the main cell types in the prostate (they form the prostate glands) and they come in two forms: basal and luminal. When they compared the gene expression profiles of the prostate cancer cells to healthy prostate epithelial cells, they found that the cancer cells had a similar profile to normal prostate epithelial basal stem cells.

Image of a prostate cancer tumor. Green and red represent different stem cell traits and the yellow areas show where two stem cell traits are expressed together. (Image credit: UCLA Broad Stem Cell Research Center)

Image of a prostate cancer tumor. Green and red represent different stem cell traits and the yellow areas show where two stem cell traits are expressed together. (Image credit: UCLA Broad Stem Cell Research Center)

In fact, they discovered a 91-gene signature specific to the basal stem cells in the prostate. This profile included genes important for stem cell signaling and invasiveness. That meant that the metastatic prostate cancer cells also expressed “stem-like” genes.

First author Bryan Smith explained how their results support similar findings for other types of cancers. “Evidence from cancer research suggests that aggressive cancers have stem–cell-like traits. We now know this to be true for the most aggressive form of prostate cancer.”

So what does this study mean for prostate cancer patients? I’ll let Dr. Witte answer this one…

Treatments for early stage prostate cancer are often successful, but therapies that target the more aggressive and late-stage forms of the disease are urgently needed. I believe this research gives us important insight into the cellular nature of aggressive prostate cancer. Pinpointing the cellular traits of cancer — what makes those cells grow and spread — is crucial because then we can possibly target those traits to reverse or stop cancer’s progression. Our findings will inform our work as we strive to find treatments for aggressive prostate cancer.


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