The E-Cigarette Epidemic

The Centers for Disease Control (CDC) and state health departments are currently investigating hundreds of cases of vaping-related illnesses across the country. Vaping has been linked to at least 18 deaths, but the investigations have yet to pinpoint a single ingredient or product as the cause of the illnesses. In addition to the health risks posed by inhaling the vapor, e-cigarette and vape device batteries have been reported to catch fire and cause severe injuries and death

E-cigarettes refer to a group of products that users insert a cartridge into. The cartridge contains liquid nicotine, which when heated, creates a vapor that users inhale. Millions of Americans reportedly use e-cigarettes, and in 2018 more than 3.6 million U.S. middle and high school students reported that they had used e-cigarettes in the past 30 days, according to the CDC. 

In August, the Washington Post reported that state and federal health officials were investigating approximately 100 cases of lung illnesses that they believed were linked to vaping and e-cigarette use. Gregory Conley, the president of the American Vaping Association, believes that these illnesses are linked to vaping “home brews” or “street vapes” that contain THC or illegal drugs, rather than the nicotine found in commercially available e-cigarettes. 

Patients who have been treated for these diseases initially presented with symptoms that appeared manageable and were consistent with viral infections or pneumonia, such as shortness of breath, coughing, and fever. However, they would deteriorate despite treatment with antibiotics and oxygen. Some went into respiratory failure and required ventilators. On August 23, Illinois officials reported the first vaping related death in the United States. 

While most people believe that e-cigarettes are safer than smoking traditional cigarettes, they still pose health risks. Although there are fewer chemicals and toxic substances present in e-cigarettes, they contain nicotine, a highly addictive substance. Additionally, users have been known to use the products to smoke “home brews,” which may contain other harmful ingredients. 

Due to the recent emergence of e-cigarettes, there is little research available on the long-term effects of using the devices. But, in light of recent cases, several states have issued health warnings about the devices, as well as temporary bans on the use of flavored vapes, and Massachusetts has issued a four-month ban on the sale of vaping products. 

Nano-Immunotherapy Treats Glioblastomas

Glioblastomas are the most common type of brain tumors in adults. They’re difficult to treat due to their location, making them one of the deadliest cancers. The tumors are aggressive, forming new blood vessels and growing rapidly and they can also use connection fibers to spread to the other side of the brain. Treating glioblastomas is difficult, as surgery can be impossible depending on the location within the brain and few drugs can cross the blood-brain barrier to treat the tumors. 

Recently, scientists at Cedars-Sinai in Los Angeles created a treatment by combining an immuno-oncology drug and a polymer-based delivery system that is capable of crossing the blood-brain barrier. In the study, researchers tested the drug combination in mice with gliblastomas. The study’s results, published in Nature Communications, showed that the treatment, called nano-immunotherapy, was able to cross the blood-brain barrier and stopped the tumor cells from multiplying. The polymer delivered two immune checkpoint inhibitors, blocking either CTLA-4 or PD-1. When injected into the mice’s bloodstream, the drugs were able to cross into the tumor cells and treat them, but didn’t affect health brain tissue. 

Past research has shown that brain tumors are able to suppress immune attacks with macrophages and T regulatory cells (Tregs). The researchers at Cedars-Sinai found that after they treated the mice with nano-immunotherapy, the checkpoint inhibitors blocked Tregs and macrophages, allowing the tumor-killing cells to treat the tumors. 

Additional preclinical trials are needed before the nano-immunotherapy is ready to be tested on humans, but Cedars-Sinai’s Julia Ljubimova, lead author of the study, is optimistic about the results. 

“The horizon for treatment of brain cancer is getting clearer,” she said. “We hope that by delivering multifunctional new-generation drugs through the blood-brain barrier, we can explore new therapies for many neurological conditions.” 

3D Printers Improve Surgical Outcomes

Technology has led to several medical developments over the past few decades, and the industry continues to grow. One of the most important recent advances has been the use of 3D printers to help surgeons plan for procedures before the patient is in the operating room. 

Surgeons at Yale Medicine have been using a 3D printer to assist their planning before going into surgery for a number of years. One of the top uses for MakerBot, the 3D printer housed in Yale’s School of Engineering & Applied Science, is making models of knee joints and surgical instruments for knee replacements. Dr. Daniel Wiznia is an orthopedic surgeon at Yale Medicine who uses 3D-printed models to practice his surgeries before performing them on the patient. 

When planning a surgery, Dr. Wiznia inputs the patient’s data from an MRI scan into a computer program. There, he works with special software to plan where he wants to put the knee replacement, how he wants it to fit on the bone, the size of the implants and how the knee should bend. The information is then converted into a file that the 3D printer understands so that it can custom print the surgical instruments needed for the operation. Since the tools are specialized for each patient, and Wiznia has already planned how he will position the implants, he is often able to make smaller incisions. This reduces the strain put on ligaments and soft tissue, leading to less pain and blood loss and often shortens the hospital stay after surgery. 

Read all of the ways the 3D printer at Yale is helping surgeons and patients here.

Recent Study Expands Understanding of how Cyclophosphamide Works

Cyclophosphamide became known in the mid-1900s for its ability to help cure lymphoma in children. Today, researchers have a better understanding of how the drug works and its ability to combat cancer. In a recent paper published in Cancer Discovery, researchers showed that cyclophosphamide is able to both kill cancer cells and trigger the immune system, causing it to attack diseased cells. These findings are helping researchers better understand how immune cells are activated to fight cancer. 

Cyclophosphamide is an alkylating agent, one of the oldest and most common types of chemotherapy used by oncologists. Now used to treat several types of cancer, it was originally used to treat Burkitt’s lymphoma, named for the doctor who first used the drug to fight this form of lymphoma. Prior to Burkitt’s work, the disease had a 100% mortality rate. 

Alkylating agents work by attaching chemical components, called alkyl groups, to the DNA in cancer calls, causing breaks in the DNA. This makes it impossible for the cells to duplicate their DNA and divide, which, in turn, stops cellular growth. But research over the years has shown that while high doses were more effective than low doses against certain cancers, they inflicted a similar amount of DNA damage. This led researchers to believe something else was going on when high doses were being administered. 

The recent study showed the effect high doses of cyclophosphamide had on macrophages. Macrophages are cells that can attack infected or dying cells. The results in mouse models implanted with human lymphoma tissue showed that high doses of the drug damaged tumor cells in a way that stressed the lymphoma cells. The stressed cells secreted cytokines, substances that summon macrophages to destroy tumor cells. They also found that macrophages expressing the CD36 and FcgRIV proteins had the largest appetite for the stressed lymphoma cells. 

While high doses of cyclophosphamide and other alkylating agents may be too toxic for patients, researchers are looking into other drugs that mimic the tumor stress with milder side effects. 

Targeted Therapy for BPDCN

Blastic Plasmacytoid dendritic-cell neoplasm (BPDCN) is a rare and aggressive form of blood cancer that affects a type of immune cell. A recent multi-institutional clinical trial studied Tagraxofusp, a targeted biological therapy, to treat the disease. Tagraxofusp targets the CD123 protein, which is over-expressed by BPDCN tumor cells; Tagraxofusp is an interleukin-3 fused to truncated diphtheria toxin. The study’s results were positive and after they were published in the New England Journal of Medicine, the FDA approved the therapy to treat BPDCN.

Each year, hundreds of people in the United States are diagnosed with BPDCN, and the disease is usually treated with chemotherapy. If the disease responds well, patients may be eligible for stem cell therapy to further treat the disease. However, since the median age of diagnosis for BPDCN is 65, many patients aren’t able to undergo intensive chemotherapy to prepare for a stem cell transplant.

Phase 1 of the trial recruited patients with BPDCN or acute myeloid leukemia (AML). They received Tagraxofusp for five days of a 21-day cycle. Forty-seven patients were treated for BPDCN by the end of the trial; 32 hadn’t been treated before and 15 had. The primary outcome of the trial for BPDCN patients was a combination of complete responses and “clinical complete responses” among previously untreated patients.

Of the twenty-nine previously untreated patients in the trial who received Tagraxofusp, 45 percent were able to receive stem cell transplants. The trial treated patients up to the age of mid-80s and found no obvious difference in toxicity by age, unlike standard chemotherapy. For patients who didn’t respond well enough to have a stem cell transplant, many stayed on Tagraxofusp for several cycles.

The trial found that the most significant side effect of Tagraxofusp was capillary leak syndrome, which can be dangerous. To deal with this, researchers altered the inclusion criteria for patients to require that they have normal cardiac function and also established procedures to detect and treat the syndrome while patients were taking Tagraxofusp.

Nine cancer centers participated in the study and drew patients from around the world.

“We can celebrate this new drug; it’s great to have approval,” said Andrew Lane, co-first author of the paper and director of Dana-Farber’s BPDCN Center. “Still, we continue to work on improving outcomes for patients.”

New Treatment Offers Mesothelioma Patients Hope

Last month, the U.S. Food & Drug Administration (FDA) approved the NovoTTF-100L system, a new first-line therapy for treating malignant pleural mesothelioma. This is the first treatment for mesothelioma to receive approval in over 15 years. NovoTTF-100L uses Tumor Treating Fields, a type of therapy that emits electric currents to disrupt cancer cell division and tumor growth.

NovoTTF-100L was created by Novocure and approved under the FDA’s Humanitarian Device Exemption eight months after Novocure released results from the STELLAR phase 2 clinical trial. The STELLAR trial was carried out at cancer centers across Europe and included 80 patients with unresectable, previously untreated malignant pleural mesothelioma. Results in the trial showed that patients treated with NovoTTF-100L survived six months longer, on average, than patients receiving only chemotherapy. There were  no reported major side effects or system toxicities, although 46 percent of patients noted skin irritation from using the device, but only 4 percent reported grade 3 skin irritation.

Ninety-seven percent of patients saw a clinical benefit from using the system, including either a partial response or stable disease. The median overall survival for patients with epithelioid mesothelioma – the most common cell type – was 21.2 months. Patients with sarcomatoid or biphasic cell types survived 12.1 months on average. Patients in the Tumor Treating Fields group saw a progression-free survival of 7.6 months, compared to 5.7 months for the chemotherapy group only.

The FDA approved the Tumor Treating Fields delivery system for use in combination with pemetrexed and platinum-based chemotherapy for unresectable, locally advanced or metastatic malignant pleural mesothelioma. NovoTTF-100L uses low-intensity alternating electric fields, which are calibrated to interfere with the division of cancer cells. For mesothelioma patients, the currents are delivered noninvasively to the upper torso and the system is intended for home use.

This is an important breakthrough for mesothelioma patients, as only 10 to 20 percent of patients qualify for tumor reduction surgery, according to Asbestos.com. In 2011, the FDA approved Optune, another Tumor Treating Fields device, for the treatment of glioblastomas.

Vitamin D Helps Slow Colorectal Cancer Progression

Results from the SUNSHINE trial by researchers at the Dana-Farber Cancer Institute suggest that supplementing chemotherapy treatments with high doses of vitamin D may help delay the progression of metastatic colorectal cancer. The study’s initial findings were reported at the 2017 American Society of Clinical Oncology meeting and have since been published in JAMA. A larger trial at hundreds of sites across the United States is set to begin later this year.

The SUNSHINE trial tested the effects of different doses of vitamin D in 139 patients being treated with chemotherapy for colorectal cancer. One group of patients received 4,000 IU of vitamin D per day and the other group received 400 IU of vitamin D per day. The high-dose group had a median delay of 13 months before their disease progressed, and the low-dose group had a median delay of 11 months. Patients in the high-dose group were also 36% less likely to have disease progression or death during the follow up period of 22.9 months.

“The results of our trial suggest an improved outcome for patients who received vitamin D supplementation, and we look forward to launching a larger trial to confirm these exciting and provocative findings,” said Charles Fuchs, MD, MPH, formerly of Dana-Farber as senior author of the study and now Director of the Yale Cancer Center.

Vitamin D is necessary for bone health and is made by the body through a chemical reaction that depends on sun exposure and is also found in some foods. Laboratory studies have shown vitamin D to have anti-cancer properties, including triggering programmed cell death, inhibiting cancer cell growth and reducing metastatic potential.

Further analysis of the results found that the of high-doses of vitamin D were less beneficial to patients who were overweight or whose tumors contained a mutated KRAS gene. These findings suggest “that certain subsets of patients may need even higher doses of vitamin D for anti-tumor activity,” according to researchers.

Kimmie Ng, corresponding author of the SUNSHINE study, feels that the findings are important because “it identifies a cost-effective, safe, and easily accessible agent as a potential new treatment for metastatic colorectal cancer. This could therefore potentially have a large and wide-reaching impact globally, regardless of a patient’s socioeconomic status or a country’s resources.”

Helicase May be Next Cancer Treatment Target

Understanding DNA mutations is the backbone of cancer research, and many recent studies have focused on new ways to combat these mutations. A study published in Nature, led by members of the Cancer Dependency Map (DepMap) Project, found that the WRN gene is a molecular vulnerability shared by several cancer types, including colon, gastric, endometrial and ovarian.

Cells with a WRN dependency have a genetic feature called a microsatellite instability (MSI). This predisposition to mutation is only seen in cancer cells and is caused by a breakdown of one of the cell’s methods for repairing damaged DNA, called mismatch repair. Approximately 15% of colon cancers, 22% of gastric cancers, 20-30% of endometrial cancers and 12% of ovarian cancers diagnosed each year lack mismatch repair and possess MSI features.

About half of cancers with MSI features can be treated using checkpoint inhibitors. The DepMap research team focused on cancers that are unresponsive to checkpoint inhibitors to determine if the loss of mismatch repair activity that leads to MSI causes genetic dependencies in tumor cells. To study this phenomenon, researchers examined two genome-scale datasets: a CRISPR-Cas9 gene dataset from the DepMap project and an RNA set created by Project DRIVE.

There were 900 cancer cell lines in these datasets, 51 of which the researchers classified as MSI. Of these, the team found that 73% of the MSI lines depended on WRN. They also found that non-MSI cancer cell lines were relatively unaffected by WRN loss. When the team changed cells to turn off WRN expression, they discovered MSI cancers grew slower, but healthy cells were unaffected.

WRN creates a helicase, an enzyme that helps cells interpret DNA. No drugs currently exist to attack WRN, but it may soon become a target given the study’s results. Since the study showed that healthy, genetically stable cells can withstand the loss of WRN, drugs created to block the enzyme should impact cancer cells that are dependent on the enzyme without harming healthy cells. The loss of WRN can lead to Werner Syndrome, but researchers believe using medications for a short period of time should mitigate this risk.

“We’re hopeful that these findings will spark excitement among other academic and drug discovery teams, and that we can help push forward a treatment that will make a difference in patients,” co-senior author and DepMap associate director Francisca Vazquez said. “And more broadly, these findings illustrate how a cancer dependency map can help identify therapeutic targets and accelerate the development of precision cancer medicine.”

Targeted Therapies Prove Effective Against Head and Neck Cancers

Each year, more than 500,000 people are diagnosed with cancers of the head and neck. A recent study by researchers at Yale Cancer Center has identified a potential protocol that combines two targeted therapies to attack head and neck cancer. These cancers are known to be particularly difficult for patients, even those who are cured, as they can alter people’s appearances and their ability to eat and speak.

Cancer is generally the result of increased cell growth and proliferation, and one of the key proteins involved in that process is the Aurora kinase A (AURKA) protein. AURKA is responsible for regulating part of the cell cycle and interacting with p53-family proteins. Another important protein in a cell’s life cycle is the WEE1 protein. Both the AURKA and WEE1 proteins are involved in in these key cellular processes. During one phase of the cycle, the dividing cell creates “spindles” that help pull apart the two sets of DNA. AURKA is needed for the spindles to work properly, and WEE1 encourages the final separation of the cells.

Many cancer patients appear to show an increased level of the AURKA protein, but high AURKA levels may be associated with worse outcomes in patients with head and neck cancers. Researchers developed an ARUKA inhibitor called alisertib, but it was not effective on its own so researchers returned to the lab to look for other drugs to combine it with.

Research has shown that the WEE1 protein is able to boost the effects of cisplatin chemotherapy on head and neck tumors with p53 mutations and resulted in the creation of a WEE1 inhibitor called adavosertib. Researchers at Yale wondered if combining inhibitors for both the AURKA and WEE1 proteins could create a “synthetic lethal effect” against head and neck cancer.

Jong Woo Lee, PhD, the lead author of the paper, experimented with the combination of alisertib and adavosertib in human cells that had non-HPV-associated head and neck cancers and found that it killed more cells than either inhibitor on its own. Collaborators studied the effect further through in vivo models, in which tumors created from human cells were grafted into mouse models, and they found that the drug combination stopped tumor growth in these models.

Researchers are now designing an early clinical trial of the drug combination for patient testing. In a second trial, they plan to examine the effects of giving each drug alone, as well as in combination, to patients before surgery. The broad goal of the studies is to determine if combining AURKA and WEE1 inhibitors can act like a synthetic lethal therapy in other cancers that depend on AURKA and have p53 mutations.

Study Suggests New Standard for Kidney Cancer

Investigators at the Dana-Farber Cancer Institute recently completed a phase 3 clinical trial that could lead to changes in the standard treatment protocol for advanced kidney cancer. The trial tested a combination of the immunotherapy medication, avelumab, and axitinib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), against sunitinib, another VEGFR TKI, which is currently the standard treatment for advanced clear-cell renal carcinoma, the most common form of kidney cancer.

This trial was the first to combine avelumab with an agent that targets one of the receptors controlling angiogenesis. VEGFR inhibitors, like axitinib and sunitinib, are designed to block the blood supply to tumors, starving them of essential nutrients. Immunotherapy medications, like avelumab, block an immune checkpoint called PD-L1, and activate the body’s T-cells so they are more effective in fighting cancer cells.

The randomized study consisted of 886 patients with previously untreated, advanced renal cell carcinoma. Results of the study showed that patients receiving the combination of avelumab and axitinib had a higher response rate than those receiving sunitinib, causing greater tumor shrinkage. The results for patients whose cancer cells were positive for the PD-L1 checkpoint showed a median progression-free survival (PFS) of 13.8 months in the combination group compared to 7.2 months in the sunitinib group. The PFS for the overall population was the same for the combination group, and was 8.4 months in the sunitinib group. Tumor shrinkage was 55.2% in the combination group compared to 25.5% in the sunitinib group who were positive for PD-L1.  

While PFS improved with the drug combination, researchers plan to continue follow ups with patients to determine if the combination of medications extends the overall survival rate compared to the standard regimen. Senior author of the study, Toni Choueiri, MD, hopes the results will lead to an FDA approval for the combination in the near future and a shift in the standard of care for patients with this difficult-to-treat cancer.