Research could lead to similar treatments for other diseases, as well as creating a demand for a new line of oncology tests for clinical labs and pathology groups
Cancer treatment has come a long way in the past decades, and it seems poised to take another leap forward thanks to research being conducted at Rice University in Houston. Molecular scientists there have developed what they call a “molecular jackhammer” that uses special molecules and near-infrared light to attack and kill cancer cells.
The technique has been effective in research settings. Should it be cleared for use in patient care, it could change the way doctors treat cancer patients while giving clinical laboratories a new diagnostic tool that could guide treatment decisions.
The researchers “found that the atoms of a small dye molecule used for medical imaging can vibrate in unison—forming what is known as a plasmon [a quantum of plasma oscillation]—when stimulated by near-infrared light, causing the cell membrane of cancerous cells to rupture,” a Rice University news release noted.
The small dye molecule is called aminocyanine, a type of fluorescent synthetic dye that is already in use in medical imaging.
“These molecules are simple dyes that people have been using for a long time,” said physical chemistry scientist Ciceron Ayala-Orozco, PhD, the researcher who led the study, in the news release. “They’re biocompatible, stable in water, and very good at attaching themselves to the fatty outer lining of cells. But even though they were being used for imaging, people did not know how to activate these as plasmons.”
“The method had a 99% efficiency against lab cultures of human melanoma cells, and half of the mice with melanoma tumors became cancer-free after treatment,” according to the Rice University news release.
“I spent approximately four years working with these ideas on using molecular forces and what is called blue-light activated molecular motors,” Ciceron Ayala-Orozco, PhD (above), told Oncology Times. “At some point, I connected the dots that what I wanted to do is use a simple molecule, not necessarily a motor, that absorbs NIR light in similar ways as plasmonic nanoparticles do and go deeper into the tissue. When activated, we found that the molecules vibrate even faster than our minds can imagine and serve as a force to break the cancer cells apart.” Once approved for use treating cancer patients, clinical laboratories working with oncologists may play a key role in diagnosing candidates for the new treatment. (Photo copyright: Rice University.)
How the Technique Works
Nuclei of the aminocyanine molecules oscillate in sync when exposed to near-infrared radiation and pummel the surface of the cancer cell. These blows are so powerful they rupture the cell’s membrane sufficiently enough to destroy it.
“The speed of this type of therapy can completely kill the cancer much faster than, say, photodynamic therapy,” Ayala-Orozco noted. “The mechanical action through the molecular jackhammer is immediate, within a few minutes.”
One advantage to near-infrared light is that it can infiltrate deeper into the body than visible light and access organs and bones without damaging tissue.
“Near-infrared light can go as deep as 10 centimeters (four inches) into the human body as opposed to only half a centimeter (0.2 inches), the depth of penetration for visible light, which we used to activate the nanodrills,” said James Tour, PhD, T. T. and W. F. Chao Professor of Chemistry, Professor of Materials Science and NanoEngineering at Rice University, in the news release. “It is a huge advance.”
The molecular plasmons identified by the team had a near-symmetrical structure. The plasmons have an arm on one side that does not contribute to the motion, but rather anchors the molecule to the lipid bilayer of the cell membrane. The scientists had to prove that the motion could not be categorized as a form of either photodynamic or photothermal therapy.
“What needs to be highlighted is that we’ve discovered another explanation for how these molecules can work,” Ayala-Orozco said in the Rice news release. “This is the first time a molecular plasmon is utilized in this way to excite the whole molecule and to actually produce mechanical action used to achieve a particular goal—in this case, tearing apart cancer cells’ membrane.
“This study is about a different way to treat cancer using mechanical forces at the molecular scale,” he added.
New Ways to Treat Cancer
The likelihood of cancer cells developing a resistance to these molecular jackhammers is extremely low, which renders them a safer and more cost effective method for inducing cancer cell death.
“The whole difference about this is because it’s a mechanical action, it’s not relying on some chemical effect,” Tour told KOMO News. “It’s highly unlikely that the cell will be able to battle against this. Once it’s cell-associated, the cell is toast once it gets hit by light. Only if a cell could prevent a scalpel from being able to cut it in half, could it prevent this.
“It will kill all sorts of cell types. With our other mechanical action molecules, we’ve demonstrated that they kill bacteria; we’ve demonstrated that they kill fungi. If a person has lost the ability to move a limb, if you can stimulate the muscle with light, that would be quite advantageous. Cancer is just the beginning,” he added.
“From the medical point of view, when this technique is available, it will be beneficial and less expensive than methods such as photothermal therapy, photodynamics, radio-radiation, and chemotherapy,” said Jorge Seminario, PhD, Professor in the Artie McFerrin Department of Chemical Engineering at Texas A&M University in a news release.
“This is one of the very few theoretical-experimental approaches of this nature. Usually, research in the fields related to medicine does not use first principles quantum-chemistry techniques like those used in the present work, despite the strong benefit of knowing what the electrons and nuclei of all atoms are doing in molecules or materials of interest,” Seminario noted.
“It’s really a tremendous advance. What this is going to do is open up a whole new mode of treatment for medicine,” Tour said. “It’s just like when radiation came in [and] when immunotherapy came in. This is a whole new modality. And when a new modality comes in, so much begins to open up.
“Hopefully, this is going to change medicine in a big way,” he added.
More research and clinical studies are needed before this new technology is ready for patient care. Clinical laboratories and anatomic pathology groups will likely be involved identifying patients who would be good candidates for the new treatment. These molecular jackhammers could be a useful tool in the future fight against cancer, which is ranked second (after heart disease) as the most common cause of death in the US.
Immunotherapy device could also enable clinical laboratories to receive in vivo biomarker data wirelessly
Researchers from Rice University in Houston and seven other states in the US are working on a new oncotherapy sense-and-respond implant that could dramatically improve cancer outcomes. Called Targeted Hybrid Oncotherapeutic Regulation (THOR), the technology is intended primarily for the delivery of therapeutic drugs by monitoring specific cancer biomarkers in vivo.
Through a $45 million federal grant from the Advanced Research Projects Agency for Health (ARPA-H), the researchers set out to develop an immunotherapy implantable device that monitors a patient’s cancer and adjusts antibody treatment dosages in real time in response to the biomarkers it measures.
It’s not a far stretch to envision future versions of the THOR platform also being used diagnostically to measure biomarker data and transmit it wirelessly to clinical laboratories and anatomic pathologists.
ARPH-A is a federal funding agency that was established in 2022 to support the development of high-impact research to drive biomedical and health breakthroughs. THOR is the second program to receive funding under its inaugural Open Broad Agency Announcement solicitation for research proposals.
“By integrating a self-regulated circuit, the THOR technology can adjust the dose of immunotherapy reagents based on a patient’s responses,” said Weiyi Peng, MD, PhD (above), Assistant Professor of Biology and Biochemistry at the University of Houston and co-principal investigator on the research, in a UH press release. “With this new feature, THOR is expected to achieve better efficacy and minimize immune-related toxicity. We hope this personalized immunotherapy will revolutionize treatments for patients with peritoneal cancers that affect the liver, lungs, and other organs.” If anatomic pathologists and clinical laboratories could receive biometric data from the THOR device, that would be a boon to cancer diagnostics. (Photo copyright: University of Houston.)
Antibody Therapy on Demand
Omid Veiseh, PhD, Associate Professor of Bioengineering at Rice University and principal investigator on the project, described the THOR device as a “living drug factory” inside the body. The device is a rod-like gadget that contains onboard electronics and a wireless rechargeable battery. It is three inches long and has a miniaturized bioreactor that contains human epithelial cells that have been engineered to produce immune modulating therapies.
“Instead of tethering patients to hospital beds, IV bags, and external monitors, we’ll use a minimally invasive procedure to implant a small device that continuously monitors their cancer and adjusts their immunotherapy dose in real time,” said Veiseh in a Rice University press release. “This kind of ‘closed-loop therapy’ has been used for managing diabetes, where you have a glucose monitor that continuously talks to an insulin pump.
But for cancer immunotherapy, it’s revolutionary.”
The team believes the THOR device will have the ability to monitor biomarkers and produce an antibody on demand that will trigger the immune system to fight cancer locally. They hope the sensor within THOR will be able to monitor biomarkers of toxicity for the purpose of fine-tuning therapies to a patient immediately in response to signals from a tumor.
“Today, cancer is treated a bit like a static disease, which it’s not,” Veiseh said. “Clinicians administer a therapy and then wait four to six weeks to do radiological measurements to see if the therapy is working. You lose quite a lot of time if it’s not the right therapy. The tumor may have evolved into a more aggressive form.”
The THOR device lasts 60 days and can be removed after that time. It is designed to educate the immune system to recognize a cancer and prevent it from recurring. If the cancer is not fully eradicated after the first implantation, the patient can be implanted with THOR again.
Use of AI in THOR Therapy
The researchers plan to spend the next two and a half years building prototypes of the THOR device, testing them in rodents, and refining the list of biomarkers to be utilized in the device. Then, they intend to take an additional year to establish protocols for the US Food and Drug Administration’s (FDA) good manufacturing practices requirements, and to test the final prototype on large animals. The researchers estimate the first human clinical trials for the device will begin in about four years.
“The first clinical trial will focus on refractory recurrent ovarian cancer, and the benefit of that is that we have an ongoing trial for ovarian cancer with our encapsulated cytokine ‘drug factory’ technology,” said Veiseh in the UH press release.
The group is starting with ovarian cancer because research in this area is lacking and it will provide the opportunity for THOR to activate the immune system against ovarian cancer, which is typically challenging to fight with immunotherapy approaches. If successful in ovarian cancer, the researchers hope to test THOR in other cancers that metastasize within the abdomen, such as:
All control and decision-making will initially be performed by a healthcare provider based on signals transmitted by THOR using a computer or smartphone. However, Veiseh sees the device ultimately being powered by artificial intelligence (AI) algorithms that could independently make therapeutic decisions.
“As we treat more and more patients [with THOR], the devices are going to learn what type of biomarker readout better predicts efficacy and toxicity and make adjustments based on that,” he predicted. “Between the information you have from the first patient versus the millionth patient you treat, the algorithm is just going to get better and better.”
Moving Forward
In addition to UH and Rice University, scientists working on the project come from several institutions, including:
More research and clinical trials are needed before THOR can be used in the clinical treatment of cancer patients. If the device reaches the commercialization stage, Veiseh plans to either form a new company or license the technology to an existing company for further development.
“We know that the further we advance it in terms of getting that human data, the more likely it is that this could then be transferred to another entity,” he told Precision Medicine Online.
Pathologists and clinical laboratories will want to monitor the progress of the THOR technology’s ability to sense changes in cancer biomarkers and deliver controlled dosages of antibiotic treatments.
Pathologists can be paid for their role in identifying and recruiting patients for basket studies and reporting results of medical laboratory tests
Anatomic
pathologists who biopsy, report, and diagnosis cancer will benefit from a
better understanding of basket
studies and their application in developing cancer treatment therapies. Such
studies can lead to more documentation of the effectiveness of various therapies
for cancers with specific gene
signatures.
The US
National Library of Clinical Medicine defines basket studies as “a new sort
of clinical studies to identify patients with the same kind of mutations and
treat them with the same drug, irrespective of their specific cancer type. In
basket studies, depending on the mutation types, patients are classified into ‘baskets.’
Targeted therapies that block that mutation are then identified and assigned to
baskets where patients are treated accordingly.”
“Historically, cancer clinical trials have been centered on the treatment of cancer based on the anatomic location in the body, like breast cancer or brain cancer or lung cancer. A basket study is a novel trial design that includes patients with a certain molecular aberration regardless of location or tissue of origin of cancer in the body. The genomic revolution in oncology has fueled these studies,” Vivek Subbiah, MD, Associate Professor and Medical Director, Clinical Center for Targeted Therapy ( Phase 1 trials program), at the University of Texas MD Anderson Cancer Center in Houston, told Cancer Therapy Advisor. (Photo copyright: MD Anderson Cancer Center.)
Basket Studies Get Results
During a basket study, researchers may find that a drug’s
effectiveness at targeting “a genetic mutation at one site can also treat the
same genetic mutation in cancer in another area of the body,” noted Pharmacy
Times, which also pointed out basket studies are often starting points for
larger oncology trials about drugs.
For example, it was a basket study which found that vemurafenib (marketed as
Zelboraf), intended for treatment of V600E, a mutation of the BRAF gene, may also treat Erdheim-Chester
disease (a rare blood disorder) in patients who have the BRAF V600 gene
mutation, Pharmacy Times reported.
Additionally, the US Food and Drug Administration’s approval
of the cancer drug Vitrakvi (larotrectinib), an oral TRK
inhibitor, marked the first treatment to receive a “tumor-agnostic
indication at time of initial FDA approval,” a Bayer
news release stated. The drug’s efficacy, Pharmacy Times noted, was
found in a “pivotal” basket study.
Basket Studies, a Master Protocol Trial Design
The basket study technique is an example of a master protocol trial design. The FDA defines a master protocol as “a protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure. A master protocol may be used to conduct the trial(s) for exploratory purposes or to support a marketing application and can be structured to evaluate, in parallel, different drugs compared to their respective controls or to a single common control.”
Other master protocols include umbrella studies and platform
studies, according to Cancer Therapy Advisor, which noted that each
master protocol trial design has its own unique objectives:
Umbrella studies look at the effectiveness of
multiple drugs on one type of cancer;
Platform trials investigate the effectiveness of
multiple therapies on one disease on an ongoing basis; and
Basket studies focus on the effectiveness of one
therapy on patients with different cancers based on a biomarker.
“In contrast to traditional trials designs, where a single
drug is tested in a single disease population in one clinical trial, master
protocols use a single infrastructure, trial design, and protocol to
simultaneously evaluate multiple drugs and or disease populations in multiple
substudies, allowing for efficient and accelerated drug development,” states
the FDA draft guidance, “Master
Protocols: Efficient Clinical Trial Design Strategies to Expedite Development
of Oncology Drugs and Biologics.”
Final FDA guidance on master protocols design is expected early in 2020, an FDA spokesperson told Cancer Therapy Advisor.
While master protocol studies show promise, they generally
have small sample sizes, noted researchers of a study published in the journal Trials.
And some researchers have ethical concerns about basket studies.
Nevertheless, basket studies appear to hold promise for precision medicine.
Anatomic pathologists may want to follow some of them or find a way to get
involved through identifying clinical laboratory tests and reporting the results.
This new atlas of leukemia proteomes may prove useful for medical laboratories and pathologists providing diagnostic and prognostic services to physicians treating leukemia patients
Researchers at the University of Texas at San Antonio (UTSA) and the University of Texas MD Anderson Cancer Center created the online atlases—categorized into adult and pediatric datasets—to “provide quantitative, molecular hallmarks of leukemia; a broadly applicable computational approach to quantifying heterogeneity and similarity in molecular data; and a guide to new therapeutic targets for leukemias,” according to the Leukemia Atlases website.
In building the Leukemia Proteome Atlases, the researchers identified and classified protein signatures that are present when patients are diagnosed with AML. Their goal is to improve survival rates and aid scientific research for this deadly disease, as well as develop personalized, effective precision medicine treatments for patients.
To perform the study, the scientists looked at the proteomic screens of 205
biopsies of patients with AML and analyzed the genetic, epigenetic, and
environmental diversity in the cancer cells. Their analysis “revealed 154 functional
patterns based on common molecular pathways, 11 constellations of correlated
functional patterns, and 13 signatures that stratify the outcomes of patients.”
Amina Qutub, PhD, Associate Professor at UTSA and one of the authors of the research, told UTSA Today, “Acute myelogenous leukemia presents as a cancer so heterogeneous that it is often described as not one, but a collection of diseases.”
“To decipher the clues found in proteins from blood and bone marrow of leukemia patients, we developed a new computer analysis—MetaGalaxy—that identifies molecular hallmarks of leukemia,” noted Amina Qutub, PhD (above), UTSA Professor of Biomedical Engineering and one of the UTSA study’s authors. “These hallmarks are analogous to the way constellations guide navigation of the stars: they provide a map to protein changes for leukemia,” she concluded. (Photo copyright: UTSA.)
To better understand the proteomic levels associated with AML, and share their work globally with other scientists, the researchers created the Leukemia Proteome Atlases web portal. The information is displayed in an interactive format and divided into adult and pediatric databases. The atlases provide quantitative, molecular hallmarks of AML and a guide to new therapeutic targets for the disease.
The NCI predicts there will be approximately 21,540 new
cases of AML diagnosed this year. They will account for about 1.2% of all new
cancer cases. The disease will be responsible for approximately 10,920 deaths in
2019, or 1.8% of all cancer deaths. In 2016, there were an estimated 61,048
people living with AML in the US.
“Our ‘hallmark’ predictions are being experimentally tested
through drug screens and can be ‘programmed’
into cells through synthetic manipulation of proteins,” Qutub continued. “A
next step to bring this work to the clinic and impact
patient care is testing whether these signatures lead to the aggressive growth
or resistance to chemotherapy observed in
leukemia patients.
“At the same time, to rapidly accelerate research in
leukemia and advance the hunt for treatments,
we provide the hallmarks in an online compendium [LeukemiaAtlas.org] where fellow
researchers and oncologists worldwide can build from the resource, tools, and
findings.”
By mapping AML patients from the proteins present in their
blood and bone marrow, the researchers hope that healthcare professionals will
be able to better categorize patients into risk groups and improve treatment
outcomes and survival rates for this aggressive form of cancer.
The Leukemia Proteome Atlases are another example of the
trend where researchers work together to compile data from patients and share
that information with other scientists and medical professionals. Hopefully, having
this type of data readily available in a searchable database will enable
researchers—as well as clinical laboratory scientists and pathologists—to gain
a better understanding of AML and benefit cancer patients through improved
diagnosis, treatment, and monitoring.
Clinical laboratory managers and pathologists have an opportunity to expand the presence of laboratory medicine
IBM (NYSE: IBM) recently issued a press release announcing its new Watson Healthcare Advisory Board (WHAB). The board is comprised of healthcare leaders with a broad range of research, medical and business expertise. Unfortunately, that expertise does not include pathology or specialists in laboratory medicine.
“Watson represents a technology breakthrough that can help physicians improve patient outcomes,” said Herbert Chase, M.D., Professor of Clinical Medicine (in Biomedical Informatics) at Columbia University, in a recent IBM press release. “As IBM focuses its efforts on key areas including oncology, cardiology and other chronic diseases, the advisory board will be integral to helping align the business strategy to the specific needs of the industry.” (more…)
