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.

CA-170 May Help Fight Mesothelioma

Mesothelioma is a rare and extremely aggressive form of cancer that affects the lining around the lungs, heart and abdominal cavity. It is caused by exposure to asbestos, but symptoms often remain dormant for years or decades. It is difficult to treat and has a five-year survival rate of only 9%, according to the Mesothelioma and Asbestos Awareness Center. Recently, a new clinical trial has begun enrolling and treating mesothelioma patients with an experimental immunotherapy drug called CA-170 in hopes of improving the prognosis.

The current study is a Phase I, open-label dose-escalation and dose-expansion trial that is focusing on studying the safety and initial clinical efficacy of CA-170 in patients. Two dosages are being tested on study participants.

CA-170 is a dual inhibitor of the VISTA protein and the PDL1 protein receptor and is currently the only anti-VISTA therapy being studied. The VISTA protein is present in 90% of mesothelioma tumors and helps cancer cells avoid attack from the immune system. High levels of VISTA expression have also been noted in other cancers, including ovarian, endometrial and non-small cell lung cancer. This suggests that the results from this study could have broader impact if CA-170 proves effective against the VISTA protein.

The PDL1 receptor also stops the immune system from attacking a cancer cell. By stopping both the VISTA and PDL1 communications to the immune system that the cell shouldn’t be attacked, the immune system is able to recognize the cancerous cells and begins attacking the diseased cells.

There are several PDL1 inhibitors currently on the market, including Tecentriq and Imfinzi, which have shown promise in treating mesothelioma. Researchers hope that by combining these effects with a drug that is able to also inhibit the VISTA protein, they will be able to better treat mesothelioma tumors.

The mesothelioma cohort is actually a sub-section of a larger study that has been active since 2016. Other groups in the study are being observed for how CA-170 affects advanced solid tumors and lymphomas, but they focus on a different protein. So far, the drug has shown promising results, as it has been well tolerated with no significant toxicity, as well as preliminary signs of tumor shrinkage.

The Food and Drug Administration has not approved a new treatment for mesothelioma since 2004, when a combination of the chemotherapies, Alimta and cisplatin, became the standard treatment of choice.

What Are Tyrosine Kinase Inhibitors?

Cancer treatments have dozens of names and acronyms associated with them. Each type of cancer generally responds to a different medication, and even within a cancer type, there are subtypes depending on the mutations present in a specific tumor. Tyrosine kinase inhibitors (TKIs) are a form of targeted therapy that are used to treat many types of leukemia, as well as solid tumors such as non-small cell lung cancer (NSCLC). Targeted therapies have become extremely common in cancer treatment, because they are able to identify and attack cancer cells while causing much less damage to healthy cells.

TKIs block the action of enzymes called tyrosine kinases. Tyrosine kinases are involved in multiple cell functions, including cell signaling, growth and division. When these enzymes are overactive or mutated, they can cause cells to grow uncontrollable (resulting in cancer). TKIs work by blocking these enzymes, which, in turn, stops cancer cells from growing and helps slow  the disease down dramatically in many cases.

TKIs are used both as an initial treatment method, as well as in cases of resistance when treating cancer. Initial treatments are the first-line therapy used on a patient to treat a disease. If the initial therapy fails to work on the patient, meaning the cancer doesn’t respond or the person isn’t able to tolerate the side effects, another treatment option is often prescribed. Certain TKIs, such as imatinib mesylate and dasatinib, are used as first and second-line therapies, while other medications, such as bosutinib and ponatinib, are used generally when patients have failed one of the front-line treatments. Second- and other later line therapies are often created to specifically overcome resistances created by one or more earlier lines of treatment.

Patients with NSCLC and certain forms of leukemia are the most common recipients of TKIs. Patients with chronic myeloid leukemia (CML) are often treated with TKIs, because they are able to target the abnormal ALK or BCR-ABL protein, respectively that causes uncontrollable cell growth. TKIs block the protein’s function causing cells to stop growing and die.

TKIs are also used to treat Philadelphia chromosome-positive acute lymphoblastic eukemia (Ph+ ALL). Before the discovery of TKIs in the early 2000s, patients diagnosed with Ph+ ALL had less than a 20% chance of long-term survival. When TKIs were introduced into treatment protocols alongside standard chemotherapy, the 5-year survival rate more than doubled. Recent studies have shown that second-generation TKIs are even more effective than their predecessors at combating this disease.

Patients with NSCLC are also treated with TKIs, particularly those who have a overactive or mutated forms of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK). Studies have shown that patients treated with EGFR TKIs have improved overall response rates and progression-free survival rates, as well as a better quality of life. Recently, second-generation TKIs targeting the T790M mutation of EGFR have become available for patients with this advanced form of NSCLC.  

Molecular Vulnerabilities Discovered in Cancer

Synovial sarcomas and rhabdoid tumors are two of the most difficult types of cancer to treat. Synovial sarcomas are found in the soft tissues and are most often diagnosed in young adults. Rhabdoid tumors typically develop in the brain, kidney and other organs of children under two. Both of these cancers are deadly and have survival rates around 30 percent, but a recent discovery of a molecular vulnerability by scientists at the Dana-Farber Cancer Institute could offer new treatment options.

Researchers discovered a “molecular machine” called ncBAF that regulates gene activity. This molecular machine, called a chromatin-remodeling complex, is essential to the development and maintenance of cancer. These complexes are made of proteins that determine how DNA is packaged in a cell and regulate which genes are expressed. Researchers found that disabling components of the molecule hindered the cancer’s ability to reproduce. Dr. Cigall Kadoch was senior author of the report published in Nature Cell Biology.

Kadoch’s team focused on a group of complexes called the SWI/SNF family. They found that the molecules travel to different locations in the DNA within a cell and impact the genes that are turned on, as well as the creation of proteins. It is estimated that 20 percent of human cancers are associated with mutations in the chromatin-remodeling complex, disrupting gene expression and causing tumors to develop.

Researchers found the ncBAF complex is essential for synovial sarcoma and rhabdoid tumors to maintain cell division and growth. Researchers believe that disrupting ncBAF could be the key to treating these tumors, deeming it a “synthetic lethal target.”

Kadoch and her colleagues further focused on the BRD9 subunit of the ncBAF complex, noting that there are current treatments under investigation focused on blocking BRD9. Researchers are also working on protein degraders that are designed to eliminate BRD9 in cells. Kadoch hopes her team’s findings will assist other researchers as they work on blocking the BRD9 protein and fighting cancer.

Combatting the EZH2 Enzyme

Chemotherapy has been the standard cancer treatment method for lung cancer, but it is known to cause problems, including harming healthy cells and not killing all cancer cells. These cells are often changed as a result of the chemotherapy, making them more difficult to treat with standard methods. As a result, these cells evade further treatment, causing the cancer to return. More recently, immunotherapy with checkpoint inhibitors have become the mainstay of first line and follow on therapy in various types of lung cancers.  

A recent study by Dr. Gaetano Gargiulo at the Helmholtz Association in Germany has discovered a potential way to treat cells that have been altered by chemotherapy treatment. His research was recently published in the Journal of Experimental Medicine and focused on non-small cell lung cancer (NSCLC), the most common type of lung cancer, which includes several subtypes.

While chemotherapy is often successful in stopping cells from dividing in NSCLC patients, aggressive cancer cells can survive the treatment and end up altered as a result. These remaining cells are dangerous because they have changed in a way that can leave doctors unsure as to what type of cancer they are dealing with and how to best treat it.

Dr. Gargiulo’s team investigated an enzyme, called Enhancer of Zeste 2 (EZH2), that promotes lung cancer. They treated test mice with drugs that inhibited EZH2, and soon found that it caused the cancer cells to become more aggressive due to inflammation in the cells. Instead of seeing this as a problem, researchers saw an opportunity to outsmart the cancer. The researchers encouraged the cells to become inflamed and then ambushed them by giving the mice an anti-inflammatory drug, leaving the aggressive cells exposed and vulnerable to treatment.

Early tests suggest this could be a potential strategy to explore in treating lung cancer patients. Gargiulo made a point of noting that making cancer more aggressive can be very dangerous, and researchers must be cautious when pursuing this experimental path.