Cancer Stem Cells and How to Get Rid of Them

If you have not yet heard of cancer stem cells (CSCs), often considered to be the real culprits in cancer, it is about time you do. CSCs are stem cells found in tumors. Drugs that target them are showing promise in clinical trials. More on that later; first, let’s introduce the concept of stem cells:

All normal tissues in our bodies develop from a small number of very special cells known as stem cells. Stem cells can divide a seemingly unlimited number of times. Continue reading…

The Coming Third Wave of Precision Cancer Medicines

“Targeted treatments for cancer have been extending and saving lives for more than 15 years—precision medicine isn’t a new idea in oncology. Now drugs pioneered on select, specific cancers are, one by one, finding new applications.

“The first wave of targeted drug approvals were for cancers associated with specific mutations. Herceptin (traztuzumab) led the way, approved in 1998. It’s a monoclonal antibody deployed against the HER2/neu receptor that is overabundant in some aggressive and early-onset breast cancers. Robert Bazell’s excellent book Her 2 tells the tale.

“In 2001 came the blockbuster Gleevec (imatinib), a small molecule that intercepts signals to divide. Erin Zammett’s My So-Called Normal Life with Cancer relates that story. A very young editor at Glamour magazine when a routine check-up revealed chronic myelogenous leukemia, Erin’s recovery was one of the first of thousands thanks to this now famous drug.”

Switch from Imatinib to Nilotinib Improved Outcomes in Chronic Phase CML

Editor’s note: This story is about the results of a clinical trial – a research study with volunteer patients. The study tested a treatment for people with chronic phase chronic myeloid leukemia (CML) who had persistent minimal residual disease after long-term treatment with the drug imatinib (Gleevec). For the study, half of the 200 participants continued taking imatinib, and half of the patients switched to the drug nilotinib. It was found that the patients who switched to nilotinib had better outcomes than those who didn’t.

“Patients with chronic phase chronic myeloid leukemia who had persistent minimal residual disease after long-term treatment with imatinib achieved deeper molecular responses and undetectable disease when they switched to treatment with nilotinib, according to study results.

“The reduced disease burden associated with the switch to nilotinib may enable patients to enroll on treatment-free remission trials, researchers wrote.

“Timothy P. Hughes, MD, FRACP, FRCPA, head of the division of hematology at South Australia Pathology and clinical professor of medicine at University of Adelaide in Australia, and colleagues evaluated data from 207 patients with CML. All patients were in complete cytogenetic response yet had detectable BCR-ABL1 after 2 or more years of treatment with imatinib (Gleevec, Novartis).”

Drugs to Avoid in Patients on Tyrosine Kinase Inhibitors

Editor’s note: More and more people with cancer are being treated with drugs known as tyrosine kinase inhibitors (TKIs). As with any other drug, oncologists who prescribe TKIs must be aware of other drugs a patient is taking to ensure there will not be a dangerous drug-drug interaction. Researchers recently published a report outlining known and potential drug-drug interactions between TKIs and other drugs. Oncologists and patients may wish to take these into account when considering cancer treatment with TKIs.

“With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an “increasing risk,” according a new report.

“To guarantee the safe use of TKIs, ‘a drugs review for each patient is needed,’ write Frank G.A. Jansman, PharmD, PhD, from Deventer Hospital in the Netherlands, and colleagues in a review published in the July issue of the Lancet Oncology.

“The review provides a comprehensive overview of known and suspected interactions between TKIs and conventional prescribed drugs, over-the-counter drugs, and herbal medicines.

“All 15 TKIs approved to date by the US Food and Drug Administration or the European Medicines Agency are evaluated.

“They are axitinib (Inlyta, Pfizer), crizotinib (Xalkori, Pfizer), dasatinib (Sprycel, Bristol-Myers Squibb and Otsuka America), erlotinib (Tarceva, Osi Pharmaceuticals), gefitinib (Iressa, AstraZeneca), imatinib (Gleevec, Novartis), lapatinib (Tykerb, GlaxoSmithKline), nilotinib (Tasigna, Novartis), pazopanib (Votrient, GlaxoSmithKline), regorafenib (Stivarga, Bayer), ruxolitinib (Jakafi, Incyte), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer), vandetanib (Caprelsa, AstraZeneca), and vemurafenib (Zelboraf, Roche).”

Large-scale Analysis of PDGFRA Mutations in Melanomas and Evaluation of Their Sensitivity to Tyrosine Kinase Inhibitors Imatinib and Crenolanib

“Platelet-derived growth factor receptor alpha (PDGFRA) is a target for tyrosine kinase inhibitors (TKIs)-based targeted therapy. Dysregulation of PDGFRA has been reported in many cancers. However, PDGFRA mutations in melanomas have not been well studied. We analyzed the genetic mutations of PDGFRA in Chinese melanoma patients, and determined the inhibitory potency of TKIs such as imatinib and crenolanib on mutant PDGFRA. Experimental Design: 351 melanoma tissue samples were examined for genetic mutations in exons 12, 14 and 18 of PDGFRA. Activities of mutations in response to imatinib and crenolanib were analyzed by western blotting of tyrosine-phosphorylated PDGFRA and cell proliferation assays. Results: PDGFRA mutations were observed in 4.6% (16/351) of melanomas, and these mutations were mainly detected in acral and mucosal melanomas. PDGFRA mutations appear to be mutually exclusive with KIT mutations, but may coexist with BRAF and NRAS mutations. The genetic mutations of PDGFRA were unrelated to the age, thickness and ulceration status of primary melanomas. Thirteen mutations were not reported before, and five (P577S, V658A, R841K, H845Y and G853D) of them resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except that V658A mutation was imatinib-resistant, all the other mutations were sensitive to both imatinib and crenolanib. Conclusions: PDGFRA mutations are detected in a small population of melanoma patients. Our study suggests that melanoma patients harboring certain PDGFRA mutations may benefit from imatinib and crenolanib treatment.”

New Recommendation for Melanomas with KIT Mutations

Thanks partly to a new study, national guidelines now include a targeted treatment for melanomas with mutated KIT genes. The drug, called imatinib, is already used for chronic myelogenous leukemia. In a phase II clinical trial that included 12 people with melanomas that had KIT mutations, imatinib shrank tumors in 77%. KIT abnormalities can also include too many copies of this gene, but the drug was not effective against these tumors. KIT mutations, which are relatively uncommon, can occur in mucus membranes, extremities such as fingers, and skin with chronic sun damage. Now that there is a recommended targeted treatment, the researchers advise testing such melanomas for KIT mutations.

Another Option in Our KIT of Effective Therapies for Advanced Melanoma

“Hodi et al reported the final results of a multicenter phase II trial of imatinib in patients with advanced melanoma harboring mutations or amplification of the KIT proto-oncogene. KIT is a transmembrane receptor tyrosine kinase, normally expressed on melanocytes, that plays a critical role in melanocyte migration, survival, proliferation, and differentiation. Mutations and amplification of KIT have been identified in melanomas arising from mucosal, acral or chronically sun-damaged surfaces, and they characterize a distinct genetic subset of disease. The alterations identified are, in most instances, mutually exclusive of BRAF and NRAS mutations and lead to constitutive activation of downstream signaling pathways including the MAPK, PI3K/AKT, and JAK/STAT pathways.”

KIT-Mutated Melanomas Respond to Imatinib

“Imatinib has activity in KIT-mutated mucosal, acral, or chronically sun-damaged melanoma.”

Imatinib for Melanomas Harboring Mutationally Activated or Amplified KIT Arising on Mucosal, Acral, and Chronically Sun-Damaged Skin

“Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities…We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations…Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.