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Friday, May 10, 2019

New Cancer Therapy Target Found in Mitochondria for Potential Treatment of Blood Cancers

​A study at The University of Texas MD Anderson Cancer Center identified a new therapeutic target in cancer cells and explains how new anti-cancer drugs called imipridones work by inducing cancer cell death in blood cancers, such as acute myeloid leukemia (AML) and mantle cell lymphoma.

The study revealed a target in mitochondria, called caseinolytic protease P (ClpP), which, upon activation, breaks down proteins within mitochondria, a process known as mitochondrial proteolysis. A new class of anti-cancer agents, called imipridones, were shown to activate ClpP and cause cancer cell death via mitochondrial proteolysis.

The drugs, ONC201 and Onc212, work regardless of whether the common tumor suppressor p53 is present in any form. Findings from the study, led by Michael Andreeff, MD, PhD, Professor of Leukemia, and Jo Ishizawa, MD, PhD, Assistant Professor of Leukemia, were recently reported in an online issue of Cancer Cell (2019; https://doi.org/10.1016/j.ccell.2019.03.014).

"Despite newly developed targeted agents, the majority of hematologic malignancies and solid tumors are still incurable. This includes essentially all patients with p53 mutations," said Andreeff. "Therefore, anti-tumor agents with novel mechanisms of action are urgently needed. Our findings support the clinical development of imipridones and other ClpP activators for human cancers."

Through in vitro and in vivo models, the team demonstrated that knock-out or over-expression of inactivated mutant ClpP induced complete resistance against ONC201 and ONC212, indicating that activation of ClpP is crucial for cell death caused by the drugs. Through extensive crystallography studies, the team identified the exact binding sites and binding patters of the drugs on ClpP and demonstrated how they increased protease activity.

While ONC201 is in early clinical trials for AML and other cancers and its pre-clinical efficacy has been established in numerous cancer models, the direct target behind its success has remained elusive. Pre-clinical toxicology studies have been conducted for ONC212, and it is slated for clinical trials in the near future.

"Deletions or mutations of ClpP have never been reported in primary AML, suggesting that ClpP could be an effective target across the spectrum of molecular and cytogenetic subsets of AML," said Ishizawa. "Our data indicate that patient samples with the lowest levels of ClpP are less sensitive to ClpP hyperactivation. Thus, levels of ClpP could serve as a biomarker to identify AML patients most likely to respond to this therapy."

Andreeff added that further studies of larger numbers of patients will be required to establish thresholds of ClpP expressions most likely to predict response.

MD Anderson study team members included: Takenobu Nii, PhD; Ran Zhao; Lauren Heese; Vivian Ruvolo; Yuki Nishida, MD, PhD; Kensuke Kojima, MD, PhD; Gautam Borthakur, MD; and Hagop Kantarjian, MD, all of the Department of Leukemia; Eric Davis, MD; and Man Chun Ma, PhD, of the Department of Lymphoma and Myeloma; Wencai Ma, MD, PhD, of the Department of Bioinformatics & Computational Biology; and Todd Link, PhD, of the Department of Genomic Medicine.

Monday, April 22, 2019

Overlooked Molecular Machine May Help Treat Aggressive Leukemia

An international team of scientists report in Nature Cell Biology on a long-overlooked part of a leukemic cell's internal machinery called the spliceosome, where they found a hyperactive form of a protein called IRAK4 that sends cells on a cancer-causing frenzy (2019; https://doi.org/10.1038/s41556-019-0314-5).

When they targeted the hyperactive form of IRAK4 in laboratory tests to block its function in acute myeloid leukemia (AML) cells, and in patient AML cells transplanted into immunosuppressed mice, the experimental treatment led to a significant reduction of the leukemic cells. It also prolonged survival in the animal models, according to Daniel Starczynowski, PhD, the multi-institutional study's senior investigator and part of the Cancer and Blood Diseases Institute at Cincinnati Children's Hospital Medical Center.

In this study and other projects in the lab, Starczynowski and colleagues are testing existing drugs that can target hyperactive IRAK4 in leukemia cells. They also are developing a prospective drug that more effectively inhibits hyperactive IRAK4 to treat AML and its precursor disease, myelodysplastic syndromes (MDS).

Starczynowski said that, with additional preclinical research and development, the researchers would like within a few years to have their still-unnamed IRAK4 inhibitor ready for initial clinical tests in AML patients. He stressed the need for new treatments is urgent.

"There is very little we can do for these patients. Even new drugs now getting fast-tracked through the development process may only produce another 6 months of survival," Starczynowski said. "The curative option is a bone marrow transplant, but most of these patients don't qualify. The field is really desperate for something that can help these patients."

The findings in this study, including use of IRAK4-inhibiting drugs, would potentially affect a subset of about 20 percent of AML-MDS patients, according to researchers. But they say that's significant. Now that they know to look more closely at this seemingly obscure, tiny molecular machine in the cell's nucleus—the spliceosome—it creates a way to find genetic coding miscues that fuel other subsets of AML that also depend on a hyperactive IRAK4.

Sequencing in the Spliceosome

Although invisible to the naked eye, the spliceosome is important. In a process of dicing and splicing, the spliceosome edits out unnecessary snippets of RNA coding called introns or exons. It then splices the loose snipped ends of RNA back together so specific proteins will do their jobs correctly.

But in AML cells, there are mutations in the U2AF1 gene, which result in RNA splicing errors. When U2AF1 functions normally, the correct snipped ends of RNA are glued back together. But when a mutated form of U2AF1 produces incorrectly formed RNA molecules of IRAK4, it results in a version of IRAK4 protein with extra coding sequences called IRAK4-L (or long). Together they hijack the innate immune system's molecular processes and trigger oncogenesis in myeloid blood cells.

Global Research Effort

Including first author Molly Smith, a graduate student and member of the Starczynowski lab, the study was a collaboration of eight institutions in the U.S. and the University of Oxford in England. The focus on IRAK4 started over 5 years ago when Cincinnati Children's cancer biologist Kakajan Komurov, PhD—working on a separate research project—noticed that every time he analyzed cancerous cells from patients, he saw high levels of the IRAK4 protein with extra coding sequences.

After Komurov shared his observation with Starczynowski during a chance corridor encounter at work, they launched a new project that went on to include Cincinnati Children's bioinformatician Nathan Salomonis, PhD, along with Gaurav Choudhary, PhD, and Amit Verma, MD, at the Albert Einstein College of Medicine in Bronx, N.Y. Also collaborating are investigators from the NIH, the University of Cincinnati, and the Department of Medicine at Washington University in St. Louis.

Together, the team was able to combine biological testing of leukemia models in the lab and a global analysis of genetic sequencing data by using bioinformatics and systems biology. They also were able to analyze data from the NIH's Cancer Genome Atlas, essentially a digital encyclopedia of all the genes (and the known related processes) linked to cancer.

Because the preclinical results are from experiments in cell lines and mouse models, the researchers are careful to emphasize their findings may not translate clinically to human patients. Still, the researchers say they're encouraged to have come far enough that the design of new and potentially effective targeted therapies is well underway for a blood cancer that has few such options.


Monday, April 22, 2019

Researchers Develop Protein Atlas to Accelerate AML Personalized Medicine

Only about one in four people diagnosed with acute myelogenous leukemia (AML) survive 5 years after the initial diagnosis. To improve that survival rate, researchers at The University of Texas at San Antonio (UTSA) and the University of Texas MD Anderson Cancer Center created an online atlas to identify and classify protein signatures present at AML diagnosis.

The new protein classifications will help researchers and clinicians recommend better treatment and personalized medicine for patients suffering from this aggressive cancer (Nat Biomed Eng 2019; doi:10.1038/s41551-019-0387-2).

Researcher Amina Qutub, PhD, Associate Professor in the UTSA Department of Biomedical Engineering (who joined UTSA in 2018 from Rice University), and Steven M. Kornblau, MD, Professor and practicing clinician in the Department of Leukemia at MD Anderson Cancer Center, examined the genetic, epigenetic, and environmental diversity that occurs in cancerous cells due to AML. Analyzing proteomic screens of 205 patient biopsies obtained at MD Anderson Cancer Center, the researchers developed a new computational method called MetaGalaxy to categorize the protein signatures into 154 different patterns based on their cellular functions and pathways.

By approaching this challenge through the unique lens of developing a quantitative map for each leukemia patient from protein expression in their blood and bone marrow, rather than the standard lens of qualitative metrics and genetic risks alone, the research collaborators will be able to more precisely categorize patients into risk groups and better predict their treatment outcomes.

To better understand the AML hallmarks at the proteomic level and to share the results of their work with other researchers, the Qutub and her team built a web portal known as the Leukemia Proteome Atlas. Designed with input from clinical collaborators worldwide, the online portal gives oncologists and cancer scientists the tools they need to investigate AML protein expression patterns from one patient to the next. It also provides investigators around the world with leads for new leukemia research and new computational tools.

Since many genetic mutations cannot be targeted, the proteomic profiling and target identification process used in this research study will accelerate the identification of therapeutic targets. It also propels researchers much closer to the development of personalized combination therapies for patients based on their unique protein signatures.

"Acute myelogenous leukemia presents as a cancer so heterogeneous that it is often described as not one, but a collection of diseases," noted Qutub. "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. These hallmarks are analogous to the way constellations guide navigation of the stars: they provide a map to protein changes for leukemia. Our 'hallmark' predictions are being experimentally tested through drug screens and can be 'programmed' into cells through synthetic manipulation of proteins.

"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 where fellow researchers and oncologists worldwide can build from the resource, tools and findings, LeukemiaAtlas.org."


Monday, April 22, 2019

AACR 2019: Prolonged Survival Possible With Gilteritinib in FLT3 Acute Myeloid Leukemia

​By Kurt Samson

ATLANTA—The FLT3 inhibitor gilteritinib provided better survival outcomes than standard chemotherapy in patients with relapsed or refractory acute myeloid leukemia (RR-AML) carrying the FLT3 mutation, according to final results from a phase III clinical trial, presented at the American Association for Cancer Research annual meeting (Abstract CT184).

The FDA approved gilteritinib tablets in November after reviewing safety and interim response data among patients enrolled in the ADMIRAL trial, but survival data were not mature at that time. Gilteritinib became the first monotherapy to be approved for this population of AML patients. At the same time, the agency also approved a special assay for the mutation.

Final analysis showed a significant survival advantage with gilteritinib. Treated patients experienced a median 36 percent reduction in mortality compared to subjects in the chemotherapy-alone group (9.3 months vs. 5.6 months). The difference was even greater after 1 year, at 37.1 percent compared to 16.7 percent in the standard chemo group.

The combined rate of complete remission and complete remission with partial hematologic recovery—no evidence of disease and partial recovery of blood counts—was 34.0 percent with gilteritinib and 15.3 percent for patients in the chemotherapy arm.

"This survival data, combined with gilteritinib's relatively low toxicity, establishes gilteritinib monotherapy as the new standard of care for patients with relapsed or refractory FLT3-mutated AML," said Alexander E. Perl, MD, Associate Professor of Hematology/Oncology at the Perelman School of Medicine and a member of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

"The relatively low toxicity and the fact that gilteritinib is an oral therapy means physicians can manage patients in the outpatient setting, which is a paradigm shift for the treatment of this disease," Perl told a press conference.

Methodology

The randomized, phase III ADMIRAL trial was designed to determine whether gilteritinib treatment improved survival for patients with relapsed or refractory FLT3-mutated AML over standard chemotherapy regimens.

Among 371 patients enrolled in the study, 247 received gilteritinib while 124 were treated with standard chemotherapy.

At baseline, 88.4 percent of patients had FLT3-internal random duplications—mutations that carry increased risk of early relapse and poor survival. In addition, 8.4 percent had mutations in FLT3-tyrosine kinase domain, and 1.9 percent had both. Among patients, 39.4 percent had refractory AML and 60.6 percent had relapsed disease.

Patients refractory to induction chemotherapy or untreated after first relapse were randomized to continuous 28-day cycles of 120 mg/day gilteritinib or pre-randomization selected chemotherapy regimen, including low-dose cytarabine in 14.7 percent; azacitidine in 22.9 percent; mitoxantrone etoposide and cytarabine in 25.7 percent; and 26 percent treated with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin.

Overall survival and the combined rate of complete remission/complete remission with partial hematologic recovery (CR/CRh) were co-primary endpoints. Secondary endpoints were event-free survival (EFS) and CR rate; safety/tolerability was also examined. CR rates were 21.1 percent and 10.5 percent, median EFS was 2.8 months and 0.7 months in the gilteritinib and SC arms, respectively.

Compared with salvage chemotherapy, gilteritinib was generally associated with lower toxicity during the first 30 days of treatment. Adjusted for exposure duration, serious treatment-emergent adverse events (AEs) per patient year were less common with gilteritinib (7.1%) than standard chemotherapy (9.2%).

Common AEs in all subjects included febrile neutropenia (43.7%), anemia (43.4%), and pyrexia (38.6%). Grade 3 or greater adverse events in the treatment group were anemia in 19.5 percent, febrile neutropenia in 15.4 percent, thrombocytopenia in 12.2 percent, and decreased platelet counts in 22.2 percent.

'Practice-Changing'

Perl noted that about one in three AML patients in the U.S. harbor the FLT3 mutation, and those with RR-AML typically have a poor prognosis. Remission rates are low with standard chemotherapy and, when remission is achieved it tends to be of short duration, he noted. Survival rates are short and many have a poor response to salvage therapy.

Among all AML patients, 40-70 percent relapse after achieving remission with induction chemotherapy, and up to 40 percent are refractory to induction chemotherapy and do not achieve complete remission.

"Adding this to frontline therapy may generate even better results. Clinical trials testing gilteritinib in combination with other therapies, and testing gilteritinib as frontline therapy for newly diagnosed patients, has already been launched," he noted.

"The longest survival in the gilteritinib arm was seen in patients who proceeded to transplant and then resumed gilteritinib to prevent relapse. But, unfortunately, long-term survival was very uncommon on either treatment arm."

Panel moderator Louis M. Weiner, MD, Director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, commented on the findings.

"This is a practice-changing strategy, something that has been needed in the field of acute myeloid leukemia for the entire time that I have been an oncologist," he stated. "To have something like this is special and important."

Kurt Samson is a contributing writer.


Monday, April 22, 2019

FDA Approves Pembrolizumab in Combination With Axitinib as First-Line Treatment for Advanced Renal Cell Carcinoma

The FDA has approved pembrolizumab in combination with axitinib, a tyrosine kinase inhibitor, for the first-line treatment of patients with advanced renal cell carcinoma (RCC). The approval is based on findings from the pivotal phase III KEYNOTE-426 trial, which demonstrated significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) for pembrolizumab in combination with axitinib compared to sunitinib. 

Consistent results were observed across pre-specified subgroups, IMDC risk categories, and PD-L1 tumor expression status. For the main efficacy outcome measures of OS and PFS, the pembrolizumab-axitinib combination reduced the risk of death by 47 percent compared to sunitinib (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001). For PFS, the pembrolizumab-axitinib combination showed a reduction in the risk of progression of disease or death of 31 percent compared to sunitinib (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). The ORR, an additional efficacy outcome measure, was 59 percent for patients who received the pembrolizumab-axitinib combination (95% CI, 54-64) and 36 percent for those who received sunitinib (95% CI, 31-40) (p<0.0001). This is the first indication for pembrolizumab in advanced RCC, the most common type of kidney cancer, and the first anti-PD-1 therapy FDA-approved as part of a combination regimen that significantly improved OS, PFS, and ORR versus sunitinib in patients with advanced RCC.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered if appropriate. Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a pregnant woman.

"Given the aggressive nature of the disease, many patients with advanced renal cell carcinoma need additional treatment options that can help improve survival outcomes," said Brian Rini, MD, a medical oncologist at Cleveland Clinic Cancer Center and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. "Pembrolizumab in combination with axitinib offers an important new therapeutic option for physicians to consider when approaching initial treatment for patients newly diagnosed with advanced renal cell carcinoma." 

Study Details

The approval was based on data from the pre-specified interim analysis of the phase III KEYNOTE-426 trial, a randomized, multi-center, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. "Rest of the World"). Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible.

Patients were randomized (1:1) to one of the following treatment arms:

  • pembrolizumab 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily (n=432).
  • Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks (n=429).

Among the 861 patients, the study population characteristics were: median age of 62 years (range, 26 to 90); 38 percent age 65 or older; 73 percent male; 79 percent white and 16 percent Asian; 19 percent and 80 percent of patients had a baseline Karnofsky Performance Status of 70-80 and 90-100, respectively; and patient distribution by IMDC risk categories was 31 percent favorable, 56 percent intermediate, and 13 percent poor.

Treatment with the pembrolizumab-axitinib combination continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease or unacceptable toxicity. The main efficacy outcome measures were OS and PFS as assessed by BICR according to modified RECIST v1.1. Additional efficacy outcome measures included ORR, as assessed by BICR.

The trial demonstrated statistically significant improvements in OS, PFS, and ORR in patients randomized to receive the pembrolizumab-axitinib combination compared to sunitinib.

With a median follow-up time of 12.8 months (range, 0.1 to 22 months), OS was significantly improved in patients who received the pembrolizumab-axitinib combination compared to sunitinib (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001). Estimated 12-month OS rates were 90% (95% CI, 86-92) with the pembrolizumab-axitinib combination versus 78% (95% CI, 74-82) with sunitinib. Median OS was not reached with either treatment regimen. PFS was also significantly improved with the pembrolizumab-axitinib combination compared to sunitinib (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). Median PFS was 15.1 months (95% CI, 12.6-17.7) in patients receiving the pembrolizumab-axitinib combination versus 11.1 months (95% CI, 8.7-12.5) with sunitinib. In the study, the ORR was 59 percent for patients who received the pembrolizumab-axitinib combination (95% CI, 54-64) and 36 percent for those who received sunitinib (95% CI, 31-40) (p<0.0001), with a complete response rate of 6 percent and 2 percent and a partial response rate of 53 percent and 34 percent, for patients receiving the pembrolizumab-axitinib combination versus sunitinib, respectively.

Safety & Adverse Events

In KEYNOTE-426, the safety of pembrolizumab in combination with axitinib was investigated in patients with previously untreated, advanced RCC. The median duration of exposure to the combination therapy of pembrolizumab and axitinib was 10.4 months (range, 1 day to 21.2 months). Fatal adverse reactions occurred in 3.3 percent of patients receiving pembrolizumab in combination with axitinib. Serious adverse reactions occurred in 40 percent of patients receiving pembrolizumab in combination with axitinib. 

Serious adverse reactions in ≥1 percent of patients receiving pembrolizumab in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction of either pembrolizumab or axitinib occurred in 31 percent of patients; 13 percent pembrolizumab only, 13 percent axitinib only, and 8 percent both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of pembrolizumab, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). 

The most common adverse reactions (≥20%) in patients receiving in patients receiving pembrolizumab and axitinib were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).