Tag: cancer treatment

Categories : Cancer GeneticsTags :

Novel Approach Targets Pancreatic Cancers Which Depend on Mutant KRAS Gene

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KRAS Protein Structure. RAS is a family of related proteins that is expressed in all animals. KRAS is one of three RAS genes found in humans. RAS genes are mutated in approximately one-third of all human cancers. Photo by National Cancer Institute on Unsplash

Researchers have identified a novel drug that effectively thwarts pancreatic tumours that are addicted to the cancer-causing mutant KRAS gene.

Because early detection of pancreatic cancer is difficult, it has a low survival rate, accounting for just over 3% of all new cancer cases in the US, but leading to nearly 8% of all cancer deaths, according to the National Cancer Institute.

The KRAS gene was recognised more that 25 years ago as the component of Kirsten sarcoma virus responsible for oncogenesis. Since then, mutations of KRAS have been described in a large proportion of solid tumors ranging from more than 90% of pancreatic carcinomas to 20% to 30% of pulmonary adenocarcinomas.

Through a pre-clinical study, Said Sebti, PhD, associate director for basic research at VCU Massey Cancer Center, identified a novel drug that effectively thwarts pancreatic tumors that are addicted to the cancer-causing mutant KRAS gene. 

“We discovered a link between hyperactivation of the CDK protein and mutant KRAS addiction, and we exploited this link preclinically to counter mutant KRAS-driven pancreatic cancer, warranting clinical investigation in patients afflicted with this deadly disease,“ said Dr Sebti, who is also the Lacy Family Chair in Cancer Research at Massey and a professor of pharmacology and toxicology at the VCU School of Medicine. “Our findings are highly significant as they revealed a new avenue to combat an aggressive form of pancreatic cancer with very poor prognosis due mainly to its resistance to conventional therapies.”

In 90 percent of pancreatic cancers, KRAS is mutated. Prior studies have shown that some tumours harbouring mutant KRAS are in fact addicted to the mutant gene, meaning they cannot survive or grow without it. Sebti set out to discover if there is a drug that can specifically kill those tumours with a mutant KRAS addiction.

Searching for a suitable drug

Dr Sebti and colleagues used a three-pronged approach to tackle this question.

First of all, they mapped the blueprint of pancreatic cancer cells through global phosphoproteomics, showing them how the addicted and non-addicted tumours differ at the phosphoprotein level. They found two proteins, CDK1 and CDK2, which signalled which cells were addicted to mutant KRAS.

Additionally, they analysed a comprehensive database from the Broad Institute of MIT and Harvard which contains genome-wide CRISPR gRNA screening datasets. They discovered that CDK1 and CDK2 as well as CDK7 and CDK9 proteins were associated with mutant KRAS-addicted tumors.

Finally, they evaluated 294 FDA drugs to selectively kill mutant KRAS-addicted cancer cells over non-KRAS-addicted cancer cells in the lab. They determined the most effective drug in preclinical experiments was AT7519, an inhibitor of CDK1, CDK2, CDK7 and CDK9.

“Using three entirely different approaches, the same conclusion presented itself clearly to us: pancreatic cancer patients whose tumors are addicted to mutant KRAS could benefit greatly from treatment with the CDK inhibitor AT7519,” Dr Sebti said.

To further validate these findings in fresh tumours taken from pancreatic cancer patients the researchers found that AT7519 suppressed the growth of xenograft cells from five mutant KRAS pancreatic cancer patients who relapsed on chemotherapy and/or radiation therapies.

Though AT7519 had previously been tested unsuccessfully in a number of clinical trials, none of the trials were for pancreatic cancer.

“If our findings are correct and translate in humans, then we should be able to see a positive response in pancreatic cancer patients whose tumors are addicted to mutant KRAS,” Dr Sebti said.

As well as pancreatic cancer, the study authors believe these findings may also have clinical implications for colorectal and non-small cell lung cancer patients with prevalent KRAS mutations.

Source: Virginia Commonwealth University

Journal information: Kazi, A., et al. (2021) Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer. Clinical Cancer Research. doi.org/10.1158/1078-0432.CCR-20-4781.

Categories : CancerTags :

New Insights into How Kidney Cancer Cells Respond to Treatment

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Photo by National Cancer Institute on Unsplash

Researchers from the University of Michigan Rogel Cancer Center have uncovered clues as to why kidney cancers respond so differently to treatment, opening up new tailored treatment options.

Not all kidney cancers behave the same, and some have wildly differing responses to immunotherapy or other treatments – resulting in wildly different outcomes for patients.

By sequencing the RNA of individual cells within multiple benign and cancerous kidney tumors, the researchers have identified the cells from which different subtypes of kidney cancer originate, the pathways involved and how the tumor microenvironment impacts cancer development and response to treatment.

The findings, published in PNAS, could help researchers better understand renal cell carcinoma development and guide oncologists in optimising therapies for each patient.

“Single cell RNA sequencing was key to allowing us to monitor gene expression patterns in each individual cell, revealing the mechanisms at play within the tumour microenvironment that can predict overall survival,” says study author Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology and SP Hicks Professor of Pathology at Michigan Medicine.

Researchers produced gene expression atlases for normal kidney and renal cell carcinoma samples. They predicted the putative cell of origin for more than 10 subtypes of renal cell cancer. Their analysis also uncovered pathways and interactions within the tumour microenvironment that predicted if the tumour would respond to immunotherapy. These findings could help develop biomarkers to guide kidney cancer treatment.

“By understanding the cell type where a cancer originates, it may allow us to target more precise treatments for that cancer type as well as better understand response to therapy,” Dr Chinnaiyan said.

Source: University of Michigan

Journal information: “Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response,” PNAS. DOI: 10.1073/pnas.2103240118

Categories : New Compounds and TreatmentsTags :

Olaparib Excels in Breast Cancer Trial

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A clinical trial of olaparib has been shown to help keep certain early-stage, hard-to-treat breast cancers at bay after initial treatment in promising early findings.

The results were so promising they were published early, ahead of the American Society of Clinical Oncology’s annual meeting and published in the New England Journal of Medicine. 

Olaparib, sold under the name Lynparza, was found to help breast cancer patients with harmful mutations have a longer disease-free survival after their cancers had been treated with standard surgery and chemotherapy.

It was studied in patients with BRCA1 and BRCA2 gene mutations, which can not only predispose people to breast cancer if they don’t work properly, but who did not have a gene flaw that can be targeted by the drug Herceptin.

Most patients in the study also had tumours not fuelled by oestrogen or progesterone. Triple negative breast cancers are not fuelled by these two hormones nor by the gene Herceptin targets.

The new study tested Lynparza in 1836 women and men with early-stage disease who were given the drug or placebo pills for one year after surgery and chemotherapy. About 82% of participants had triple-negative breast cancer.

Independent monitors advised releasing the results after observing clear benefit from Lynparza. After three years, 86% of patients on it were alive without cancer recurrence compared to 77% in the placebo group.

The results suggest more patients should get their tumours tested for BRCA mutations to help guide treatment decisions, said ASCO president Dr Lori Pierce, a cancer radiation specialist at the University of Michigan.

Serious side effects were rare, and other less serious side effects included anaemia, fatigue and blood cell count abnormalities.

Lynparza, which is marketed by AstraZeneca and Merck, is already sold in the United States and elsewhere for treating metastatic breast cancers and for treating certain cancers of the ovaries, prostate and pancreas. It costs roughly US$14 000 per month, though what patients pay out of pocket varies depending on income, insurance and other factors.

Source: Medical Xpress

Categories : Cancer New Compounds and TreatmentsTags :

Lenvatinib Produces Impressive Results Against Tough Tumours

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Image by doodlartdotcom from Pixabay

Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI) induced a strong tumour response in patients with advanced gastrointestinal or pancreatic tumours, according to results from a phase II trial.

The study focused on previously treated advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). An overall response rate (ORR) of 29.9% was seen in the trial, with a particularly high ORR — 44.2% — in patients with pancreatic NETs. 

“This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other targeted agents, suggesting the potential value in the treatment of advanced GEP-NETs,” wrote Jaume Capdevila, MD, PhD, of Vall Hebron University Hospital in Barcelona, and colleagues.

TKIs are a group of pharmacologic agents that disrupt the signal transduction pathways of protein kinases by several modes of inhibition. Since sunitinib maleate (Sutent), another multitargeted TKI, was approved ten years ago, investigators have been evaluating newer-generation TKIs that target VEGF receptors (VEGFRs), among other receptors, both in pancreatic and non-pancreatic NETs.

Lenvatinib targets VEGFR 1-3, fibroblast growth factor receptors (FGFR) 1-4, and platelet-derived growth factor receptor alpha.

The researchers noted that studies have demonstrated its particular effectiveness against FGFR-1, which is a key driver of resistance to antiangiogenic drugs, “suggesting that it could potentially also reverse primary and acquired resistance to anti-VEGFR treatments or to other targeted agents.”

A total of 111 patients were enrolled in the study; 55 had histologically confirmed grade 1-2 pancreatic NETs, while 56 had gastrointestinal NETs. Patients were administered 24-mg lenvatinib once daily until disease progression or treatment intolerance. Median follow-up was 23 months.

The ORR was 16.4% for patients with gastrointestinal NETs, and median duration of response was 19.9 months for patients with pancreatic NETs and 33 months for gastrointestinal NETs. The median progression-free survival (PFS) for both groups was 15.7 months.

These results compare well with PFS outcomes reported in phase III trials, including those evaluating sunitinib and surufatinib, the authors noted.

“Interestingly, the ORR in pancreatic NETs was 44%, a rate not seen before with targeted agents,” Jonathan Strosberg, MD, head of the neuroendocrine tumor division at Moffitt Cancer Center in Tampa, told MedPage Today.

Dr Strosberg, who was not involved with this research, noted that the study group had been heavily treated beforehand, and that 29% had received prior sunitinib. “In contrast, the response rates with other TKIs have been <20% in this population, even in less heavily treated populations. The ORR for gastrointestinal NETs was more modest, but still impressive,” he added.

The most common grade 3/4 adverse events was hypertension (22.7%), while a majority of patients needed either a dose reduction or a pause.

“This suggests that lower starting doses might be considered in this population, and that particularly close monitoring of blood pressure is necessary,” said Dr Strosberg.

The study results “suggest that lenvatinib is more than just a ‘me-too’ competitor to sunitinib,” he noted. “It actually seems to have superior activity, potentially due to its ability to target both the VEGF and FGF receptors. Moreover, it appears to have activity in patients who have progressed on sunitinib. Randomized phase III studies with this drug are warranted, both for pancreatic and GI/lung NETs.”

Source: MedPage Today

Journal information: Capdevila J, et al “Lenvatinib in patients with advanced grade 1/2 pancreatic and gastrointestinal neuroendocrine tumors: results of the phase II TALENT trial (GETNE1509)” J Clin Oncol 2021; DOI: 10.1200/JCO.20.03368.

Categories : CancerTags :

Nanoparticles Deliver Chemotherapy to Cancer Cell’s Doorsteps

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Fanciful depiction of nanoparticles. Photo by Landon Arnold on Unsplash

New research has developed a nanoparticle system that can deliver large, unwieldy protein-based chemotherapy drugs right to the doorsteps of cancer cells.

Some cancer treatments make use of antibodies’ ability to recognise specific cancer cells in order to target those cells with small active agents, but have not been able to deliver larger protein-based drugs.

Research published in the journal Angewandte Chemie shows how, using a new protein transport system, proteins can arrive at their target intact, protected from destructive proteases by polymer brushes.

Two problems keep coming up when scientists try to develop new anticancer drugs. Firstly, an active agent needs to be able to kill the body’s cells at the root of the cancer, and secondly it should be active in target cancer cells rather than in healthy cells. To this end, some medical researchers are  trying to implement a cargo package as a method of delivery. The active agent stays protected and packaged until it reaches the target location, while antibodies that only attach to cancer cells help with “finding the right address”. 

These antibodies recognise specific receptor structures on the outer membrane of cancer cells, attaching to these structures with the cell absorbing the active agent. However, this strategy is unsuccessful when the active agents are large proteins. 

These large proteins are usually water soluble, and unable to penetrate the cell membrane. The body’s own protease enzymes throw in another complication, because they break down the protein cargoes before they can reach their target location.

Sankaran Thayumanavan and colleagues at the University of Massachusetts in Amherst, USA, have now developed a protected nanosized cargo package, which meets both requirements of targeted delivery and keeping the cargo intact. For the container, they use miniscule beads made of silicon dioxide with a diameter of just 200 nanometres. The surface of these beads is coated with brush-like polymer strands made of polyethylene glycol (PEG) that can be doubly functionalised, giving tiny “brush beads”. This is termed a protein-antibody conjugate (PAC).

With simple click chemistry, the researchers attach the desired active-agent protein and antibodies to the polymer bristles. The finished bead-shaped packages have antibodies on the outermost layer, with the proteins safely concealed in the forest of polymer strands.

Besides the ability to transport water-soluble proteins, this PAC also possessed another advantage: a possible high protein-antibody ratio. The researchers said that, at least in theory, over 10 000 proteins could be transported per (expensive) antibody using the researchers’ PACs, compared to the maximum of four active agents per antibody in previous antibody-drug combinations.

The team tested their system on various cell cultures with different antibodies and test proteins. The test was a success; the PACs delivered their deadly cargoes to their cellular targets as planned.
The team is now going to figure out if and how the packages can be shielded from macrophages. They are optimistic about this because the PEG functionalities and the surface antibodies are designed for a quick delivery while minimising clearance by macrophages.

Source: News-Medical.Net

Journal information: Liu, B., et al. (2021) Protein–Antibody Conjugates (PACs): A Plug‐and‐Play Strategy for Covalent Conjugation and Targeted Intracellular Delivery of Pristine Proteins. Angewandte Chemie International Edition. doi.org/10.1002/anie.202103106.

Categories : CancerTags :

New Radiotherapy Treatment for Metastatic Cancers is Safe

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MRI machine. Image by Michal Jarmoluk from Pixabay

A phase I trial showed that stereotactic body radiotherapy (SBRT) proved safe for treating cancer patients with multiple metastases. However, some late adverse effects underscored the need for long-term follow-up.

SBRT is a new radiotherapy treatment method that delivers high doses of ionising radiation to tumours with great precision, minimising damage to other parts of the body while killing tumour cells.

Increasingly used by clinicians, SBRT can improve survival in cancer patients with multiple metastases, explained first author Steve Chmura, MD, PhD, of University of Chicago Medicine, and colleagues, but there is little evidence as to its safety in this application.

“Existing data include mostly treatment of 1 or 2 metastases separated widely from each other and use of differing radiation doses, toxicity reporting, image guidance, and normal tissue constraints,” they wrote. “Given the critical need, NRG Oncology NRG-BR001 trial sought to determine the safety of delivering curative-intent SBRT to patients with 3 to 4 metastases or 2 metastases within close proximity to each other.”

Patients in the study had metastatic breast, prostate, or non-small-cell lung carcinoma (NSCLC). Each metastasis was assigned to a metastatic location based on the potential for toxicity.

Dose-limiting toxicity (DLT; side effects severe enough to discontinue treatment) was the primary study outcome, defined as specific AEs of grades 3 to 5 related to SBRT within 180 days of treatment. Dose levels were considered to be safe if DLTs were seen in no more than one of six patients per location with metastases.

Of the evaluable 35 patients, 12 (34.3%) had breast cancer, 10 NSCLC (28.6%), and 13 (37.1%) prostate cancer, with a median of three metastases per patient.

DLT analysis WAS based on six evaluable patients in all of the metastatic locations save the liver (five evaluable patients). The authors reported there were no protocol-specified DLTs in any of the seven metastatic locations within 180 days of the initiation of treatment.

There were 50 grade 3 or 4 AEs reported in 18 patients, and eight were deemed to be linked to the treatment. Of those eight, six (including bone pain, pulmonary fibrosis, bronchial fistula, bronchial stenosis, spinal fracture, and humeral fracture) were reported in six patients over 180 days from the start of the treatment. No treatment-related deaths occurred, according to the authors.

The authors suggested that, with the number of late AEs reported in this trial, patients should be monitored closely for late toxic effects.

“Given the potential for ablative radiotherapy to improve outcomes of patients with oligometastatic cancer, the finding that SBRT is safe when delivered to 3 to 4 metastases or 2 metastases in close proximity to one another is important, and serves as the foundation for ongoing randomized trials,” wrote the authors. They noted that these include studies such as the phase II/III NCI-sponsored NRG-BR002 trial.

Source: MedPage Today

Journal information: Chmura S, et al “Evaluation of safety of stereotactic body radiotherapy for the treatment of patients with multiple metastases” JAMA Oncol 2021; DOI: 10.1001/jamaoncol.2021.0687.

Categories : CancerTags :

Iron is a ‘Double-edged Sword’ For Cancer Cells

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A grant by the American Cancer society will be used to investigate the treatment of certain neuroblastoma by forcing them to overloading on iron.

Neuroblastoma is a cancer that forms in nerve tissue, and most commonly in the glands around the kidneys. It is the most frequently occurring childhood cancer that occurs outside the cranium. MYCN is overexpressed in 20-25% of neuroblastoma, and these cancers contribute to a considerable portion of paediatric cancer-related deaths. Recent research has shown that the MYCN gene introduces a weakness to ferroptosis-inducing drugs because MYCN draws on a lot of iron to help the cancer grow.  

“Iron is a double-edged sword in a cancer cell. It can help the cancer grow and survive, but it also creates these toxic molecules within the cell called reactive oxygen species,” explained Anthony Faber, PhD.

Reactive oxygen species (ROS) are unstable molecules that react with other molecules, causing DNA damage and cell death. This recently discovered form of cell death, largely influenced by iron accumulation, is called ferroptosis. Little is known about ferroptosis, and even less about cancers which may be vulnerable to ferroptosis-inducing drugs. By boosting cellular toxin removal systems, MYCN produces so much iron that it also creates a vulnerability to drugs which prevent cells from eliminating ROS. Blocking these toxin removal systems causes death among MYCN-amplified cells. 

“As MYCN continues to be one of the most important targets in cancer therapeutics, this study highlights a new and clinically important strategy for treating MYCN-associated cancers,” Dr Faber said.

“Fortunately, the Cancer Mouse Models Core run by Jennifer Koblinski, PhD, and Bin Hu, PhD, at Massey is spectacular and will allow us to robustly test these FDA-approved drugs in both patient-derived models and orthotopic models, where the tumors grow atop the adrenal glands similar to the way they grow in patients,” Dr Faber said.

If these models show positive results for the testing of these drugs, they can move on to clinical trials. He added that this study may have far reaching implications, as in certain small cell lung cancers and triple negative breast cancer, whose growth is driven c-MYC, a similar protein .

Source: Medical Xpress

Journal information: Konstantinos V. Floros et al, MYCN-amplified neuroblastoma is addicted to iron and vulnerable to inhibition of the system Xc-/glutathione axis, Cancer Research (2021). DOI: 10.1158/0008-5472.CAN-20-1641

Categories : Cancer GeneticsTags :

RNA Knockout Halts the Spread of Triple-negative Breast Cancer

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The University of Westminster has released a new study showing that taking out small chunks of human DNA called microRNA can reverse the spread of triple negative breast cancer cells.

The study also suggested that microRNAs could be targeted to spot and treat triple negative breast cancer. Breast cancer is the most common cancer in women, and triple negative breast cancer makes up 10-20% of cases.

MicroRNAs (miRs) have important roles in cellular functioning and signalling, and are heavily involved in the growth and metastasis of cancers. The researchers found that miR-21, a major breast cancer-related RNA, is increased in triple negative breast cancer and is also associated with metastasis.

Using CRISPR/Cas9, the researchers knocked out miR-21 from the cancer cells, and discovered that the cancer cells’ metastatic properties were reversed. They also observed that they released smaller vesicles, which release lipid blobs that play an important part in cancer spread. There was also less miR-21 carried in the vesicles, which also carry disease-related molecules to other cells.

Lead researcher Dr Pinar Uysal-Onganer of the University of Westminster, said: “This is an important study which contributes to better understanding of roles of miRs in aggressive cancer types such as triple negative breast cancer. We are now aiming to clarify the relationships between miR-21 and cancer drug resistance, which is another important factor that limits cancer cure.”

Source: Medical Xpress

Journal information: Elif Damla Arisan et al. MiR-21 is Required for the Epithelial–Mesenchymal Transition in MDA-MB-231 Breast Cancer Cells, International Journal of Molecular Sciences (2021). DOI: 10.3390/ijms22041557

Categories : Cancer Cardiovascular DiseaseTags :

Simvastatin Treatment Hope for Subtype of Ovarian Cancer

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Researchers have found that simvastatin has anti-proliferative potential against ovarian clear cell carcinoma, a highly lethal gynaecological cancer.

Dr Ingrid Hedenfalk from The Lund University explained: “Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) accounting for 5–10% of cases diagnosed in Europe and America, while the incidence in Asia is reported to be higher (10–20%).”

GTPases are a range of enzymes that hydrolyse guanosine triphosphate (GTP) to guanosine diphosphate (GDP). They are also involved in cells as switches and timers. Rho GTPases have been studied for their role in cancers. However, it is difficult to target Rho GTPases directly, so research has involved indirect strategies.

The researchers tested three cell lines of OCCC and one line of high-grade serous ovarian carcinoma (HGSOC) with simvastatin, which is a Rho GTPase interfering drug, and another GTPase interfering drug, CID-1067700, as a control. CID-1067700 is a pan-GTPase, which makes it useful as a comparator.

The research was motivated by a study which found deregulated expression of both Rho GTPases and cytoskeletal pathways in primary human OCCC tumours. The OCCC cell lines treated with simvastatin showed reduced c-Myc protein expression and signs of cell death, as well as curbing proliferation and migration.

Simvastatin could act through Rho GTPase interference as simvastatin affects the cytoskeletal integrity of OCCC cells at clinically relevant levels. However, the mechanism involved is different from Rho GTPase inhibition by CID-1067700.

However, caution is warranted with simvastatin as combination with chemotherapy may yield an antagonistic response. Further research is warranted to develop simvastatin as a potential drug candidate for the treatment of OCCC. 

Source: Oncotarget

Journal information: Arildsen N, Hedenfalk I. Simvastatin is a potential candidate drug in ovarian clear cell carcinomas. Oncotarget. 2020;11(40):3660-3674. doi:10.18632/oncotarget.27747