Scientists create “drug-like” chemical that may inhibit pancreatic cancer stem cells

John R. Cashman, Ph.D.

Supreme Court justice Ruth Bader Ginsburg’s death this past week after battling stage 4 pancreatic cancer is a grim reminder of how aggressive the disease can be. In fact, pancreatic cancer will soon be the second leading cause of cancer-related death for individuals in the United States. Unfortunately, it is known to be highly resistant to treatments that are currently available.

With the aid of CIRM-funding, John R. Cashman, Ph.D., along with a team of researchers at the Human BioMolecular Research Institute and ChemRegen, Inc. have developed a “drug-like” chemical that may change that. The newly created compound, PAWI-2, was tested on pancreatic cancer stem cells in a laboratory setting. The compound works by activating apoptosis, a process that tells the cells when to stop dividing and influences cell death.

Under the microscope, the team of researchers found that PAWI-2 successfully inhibited the growth of these cancer stem cells. In addition to this, the team analyzed if PAWI-2 had any effect on existing pancreatic cancer treatments, specifically erlotinib and trametinib. What they found was that their “drug-like” chemical improved the effectiveness of both of these anti-cancer drugs.

In a press release, Dr. Cashman explained the significance that PAWI-2 could play for pancreatic cancer treatments.

“We need to develop effective new medications for drug resistant pancreatic cancer. Using a non-toxic small molecule like PAWI-2 to stop pancreatic cancer either by itself or in combination with standard of care chemotherapy is very appealing.”

The full paper, published in Investigational New Drugs, can be accessed here.

Blocking pancreatic cancer stem cells

John Cashman

Cancer stem cells are one of the main reasons why cancers are able to survive surgery, chemotherapy and radiation. They are able to hide from those therapies and, at a future date, emerge and spread the cancer in the body once again.

Jionglia Cheng, PhD.

Jionglia Cheng, PhD., the lead author of a new CIRM-funded study, says that’s one of the reasons why pancreatic cancer has proved so difficult to treat.

“Pancreatic cancer remains a major health problem in the United States and soon will be the second most common cause of mortality due to cancer. A majority of pancreatic cancer patients are often resistant to clinical therapies. Thus, it remains a challenge to develop an efficacious clinically useful pancreatic cancer therapy.”

Dr. Cheng, a researcher with ChemRegen Inc., teamed up with John Cashman at the Human BioMolecular Research Institute and identified a compound, that seems to be effective in blocking the cancer stem cells.

In earlier studies the compound, called PAWI-2, demonstrated effectiveness in blocking breast, prostate and colon cancer. When tested in the laboratory PAWI-2 showed it was able to kill pancreatic cancer stem cells, and also was effective in targeting drug-resistant pancreatic cancer stem cells.

In addition, when PAWI-2 was used with a drug called erlotinib (brand name Tarceva) which is commonly prescribed for pancreatic cancer, the combination proved more effective against the cancer stem cells than erlotinib alone.

In a news release Dr. Cheng said: “In the future, this molecule could be used alone or with other chemotherapy albeit at lower doses, as a new therapeutic drug to combat pancreatic cancer. This may lead to much less toxicity to the patient,”

The study is published in the journal Scientific Reports.

Stories that caught our eye: Spinal cord injury trial milestone, iPS for early cancer diagnosis, and storing videos in DNA

Spinal cord injury clinical trial hits another milestone (Kevin McCormack)
We began the week with good news about our CIRM-funded clinical trial with Asterias for spinal cord injury, and so it’s nice to end the week with more good news from that same trial. On Wednesday, Asterias announced it had completed enrolling and dosing patients in their AIS-B 10 million cell group.

asterias

People with AIS-B spinal cord injuries have some level of sensation and feeling but very little, if any, movement below the site of injury site. So for example, spinal cord injuries at the neck, would lead to very limited movement in their arms and hands. As a result, they face a challenging life and may be dependent on help in performing most daily functions, from getting out of bed to eating.astopc1

In another branch of the Asterias trial, people with even more serious AIS-A injuries – in which no feeling or movement remains below the site of spinal cord injury – experienced improvements after being treated with Asterias’ AST-OPC1 stem cell therapy. In some cases the improvements were quite dramatic. We blogged about those here.

In a news release Dr. Ed Wirth, Asterias’ Chief Medical Officer, said they hope that the five people treated in the AIS-B portion of the trial will experience similar improvements as the AIS-A group.

“Completing enrollment and dosing of the first cohort of AIS-B patients marks another important milestone for our AST-OPC1 program. We have already reported meaningful improvements in arm, hand and finger function for AIS-A patients dosed with 10 million AST-OPC1 cells and we are looking forward to reporting initial efficacy and safety data for this cohort early in 2018.”

Asterias is already treating some AIS-A patients with 20 million cells and hopes to start enrolling AIS-B patients for the 20 million cell therapy later this summer.

Earlier diagnosis of pancreatic cancer using induced pluripotent stem cells Reprogramming adult cells to an embryonic stem cell-like state is as common in research laboratories as hammers and nails are on a construction site. But a research article in this week’s edition of Science Translational Medicine used this induced pluripotent stem cell (iPSC) toolbox in a way I had never read about before. And the results of the study may lead to earlier detection of pancreatic cancer, the fourth leading cause of cancer death in the U.S.

Zaret STM pancreatic cancer tissue July 17

A pancreatic ductal adenocarcinoma
Credit: The lab of Ken Zaret, Perelman School of Medicine, University of Pennsylvania

We’ve summarized countless iPSCs studies over the years. For example, skin or blood samples from people with Parkinson’s disease can be converted to iPSCs and then specialized into brain cells to provide a means to examine the disease in a lab dish. The starting material – the skin or blood sample – typically has no connection to the disease so for all intents and purposes, it’s a healthy cell. It’s only after specializing it into a nerve cell that the disease reveals itself.

But the current study by researchers at the University of Pennsylvania used late stage pancreatic cancer cells as their iPSC cell source. One of the reasons pancreatic cancer is thought to be so deadly is because it’s usually diagnosed very late when standard treatments are less effective. So, this team aimed to reprogram the cancer cells back into an earlier stage of the cancer to hopefully find proteins or molecules that could act as early warning signals, or biomarkers, of pancreatic cancer.

Their “early-stage-cancer-in-a-dish” model strategy was a success. The team identified a protein called thrombospodin-2 (THBS2) as a new candidate biomarker. As team lead, Dr. Ken Zaret, described in a press release, measuring blood levels of THBS2 along with a late-stage cancer biomarker called CA19-9 beat out current detection tests:

“Positive results for THBS2 or CA19-9 concentrations in the blood consistently and correctly identified all stages of the cancer. Notably, THBS2 concentrations combined with CA19-9 identified early stages better than any other known method.”

DNA: the ultimate film archive device?
This last story for the week isn’t directly related to stem cells but is too cool to ignore. For the first time ever, researchers at Harvard report in Nature that they have converted a video into a DNA sequence which was then inserted into bacteria. As Gina Kolata states in her New York Times article about the research, the study represents the ultimate data archive system which can “be retrieved at will and multiplied indefinitely as the host [bacteria] divides and grows.”

A video file is nothing but a collection of “1s” and “0s” of binary code which describe the makeup of each pixel in each frame of a movie. The researchers used the genetic code within DNA to describe each pixel in a short clip of one of the world’s first motion pictures: a galloping horse captured by Eadward Muybridge in 1878.

Horse_1080.gif

The resulting DNA sequence was then inserted into the chromosome of E.Coli., a common bacteria that lives in your intestines, using the CRISPR gene editing method. The video code was still retrievable after the bacteria was allowed to multiply.

The Harvard team envisions applications well beyond a mere biological hard drive. Dr. Seth Shipman, an author of the study, told Paul Rincon of BBC news that he thinks this cell system could be placed in various parts of the body to analyze cell function and “encode information about what’s going on in the cell and what’s going on in the cell environment by writing that information into their own genome”.

Perhaps then it could be used to monitor the real-time activity of stem cell therapies inside the body. For now, I’ll wait to hear about that in some upcoming science fiction film.

Shedding Light on a Path to Halting Deadly Pancreatic Cancers

Pancreatic cancer has a dismal prognosis: only a quarter of those diagnosed survive past one year and only about six percent live beyond five years. Its strong resistance to chemotherapy makes pancreatic cancer one of the most aggressive, deadly cancers and leaves doctors with few treatment options. New ways to study pancreatic cancer are desperately needed to find novel therapies.

Today, UCSD researchers, funded in part by CIRM, report in Nature on the development of a live imaging technique that enables precise tracking of drug resistant cancer stem cells within a pancreatic tumor. Using this method, they establish that the function of a gene called Musashi (Msi) is crucial for tumor growth, making it a promising target for chemotherapy drug development.

pancreatic_cancer_imaging

Activity of stem cell gene Musashi in human pancreatic cancer. Cancer cells are shown in green, Musashi expression in red and blue includes cells within the cancer microenvironment. Image courtesy of Dawn Jaquish, UC San Diego.

The Msi protein normally plays a role in the maintenance of stem cells but it’s also known to help sustain the growth of blood cancers. The UCSD team chose to investigate the role of Msi in pancreatic cancer as they found Msi was present in every human tumor sample they tested. To track Msi in a living animal, they genetically engineered mice that would emit fluorescence in cells where the Msi gene was activated.

Cells expressing the stem cell gene Musashi (green) are shown among other tumor cells (blue) and blood vessels (pink). Musashi-expressing cells preferentially drive tumor growth, drug resistance and lethality. UCSD

Those Msi mice were then bred with another strain of mice that mimic the pancreatic cancer seen in humans. In the resulting mice, cells with a strong fluorescent signal (indicating a high level of Msi) were found as a rare, distinct population in pancreatic cancer cells. It turns out that cancer stem cells, the cells thought to be responsible for cancerous growth and treatment relapse, are also known to make up a tiny portion of a tumor. So then, do Msi-positive cancer cells have cancer stem cell-like behavior? The answer appears to be “yes”. When the team transplanted the cancer cells with high levels of Msi from one mouse into the pancreas of healthy mice, every mouse tested died from very aggressive tumor growth. On the other hand, mice transplanted with cancer cells lacking the Msi fluorescent signal showed no evidence of disease.

These very promising results, along with the new imaging toolset, not only bode well for future treatments of pancreatic cancer but also for the cancer field as a whole. In a university press release, principal investigator Tannishtha Reya detailed this point:

pancreaticTannishtha Reya

Tannishtha Reya

“Because Msi reporter [fluorescence] activity can be visualized by live imaging, these models can be used to track cancer stem cells within the tumor microenvironment, providing a real-time view of cancer growth and metastasis, and serving as a platform to test new drugs that may be better able to eradicate resistant cells.”

Let’s hope that this research path leads to the day that a pancreatic cancer diagnosis isn’t an almost certain death sentence.

Shape-Shifting Pancreas Cells Set Stage for Development of Deadly Cancer

After being diagnosed with pancreatic cancer, the likely outcome is—in a word—bleak. At a time when cancers can be treated so successfully as to give the patient a good quality of life, pancreatic cancer remains one of the last holdouts. It is the fourth most deadly form of cancer in the United States. One in four patients won’t last a year.

Pancreatic cancer is one of the most deadly forms of cancer.

Pancreatic cancer is one of the most deadly forms of cancer.

One of the main hurdles for successfully treating this type of cancer is how quickly it spreads. Oftentimes, pancreatic cancer is not diagnosed until having spread to such an extent that even the most aggressive treatments can only delay the inevitable.

As a result, the goal of researchers has been to peer back in time to the origins of pancreatic cancer—in the hopes that they can find a way to halt the disease before it begins to wreak irreversible damage on the body. And now, an international team of researchers believes they have identified a gene that could be the key culprit.

Reporting in the latest issue of Nature Communications, a joint team of scientists from the Mayo Clinic and the University of Oslo, Norway, have pinpointed a gene—called PKD1—that causes normal, healthy pancreatic cells to literally morph into a new, duct-like cell structure. And it is this change in shape that can sometimes lead to pancreatic cancer.

“As soon as pancreatic cancer develops, it begins to spread, and PKD1 is key to both processes,” said Peter Storz, one of the study’s lead authors, in a news release. “Given this finding, we are busy developing a PKD1 inhibitor that we can test further.”

The purpose of the inhibitor, says Storz, is to neutralize PKD1—stopping the cancer in its tracks.

Using pancreatic cells derived from mouse models, the research team tested the effects of PKD1 by turning it on and off at specific intervals, similar to flipping a light switch. In the presence of PKD1, the team observed the pancreas cells rapidly changing shape into the more dangerous, duct-like cells. And when they shut off PKD1, the percentage of cells that underwent shape shifting dropped.

The team’s success at developing this model cannot be understated. As Storz explained:

“This model tells us that PKD1 is essential for the initial transformation…to duct-like cells, which can then become cancerous. If we can stop that transformation from happening—or perhaps reverse the process once it occurs—we may be able to block or treat cancer development and its spread.”

Currently, the teams are developing potential PDK1 inhibitors for further testing—and bring some hope that the prognosis for pancreatic cancer may not always be so dire.

Said Storz: “While these are early days, understanding one of the key drivers in this aggressive cancer is a major step in the right direction.”