Αρχική World News Topotecan–Berzosertib Combination Shows Promise against Small Cell Lung Cancer

Topotecan–Berzosertib Combination Shows Promise against Small Cell Lung Cancer

, by NCI Staff

A small clinical trial tested the combination of topotecan with the drug berzosertib, which inhibits a protein that helps repair damaged DNA in cancer cells.

Credit: iStock

Researchers have identified a combination of two drugs that can shrink the tumors of some patients with small cell lung cancer (SCLC), the most aggressive form of lung cancer. 

Many patients with SCLC respond to an initial treatment with chemotherapy and/or immunotherapy. But the cancer usually comes back and does not respond to additional chemotherapy. At this point, the disease is typically fatal within a matter of weeks. 

The new combination therapy includes the chemotherapy drug topotecan (Hycamtin), which is FDA approved for some patients with SCLC, and the investigational drug berzosertib, which inhibits a protein that helps repair damaged DNA. 

In an NCI-supported clinical trial, the combination therapy shrank the tumors in 9 of 25 (36%) patients with SCLC whose cancer had relapsed after earlier treatment, according to results published April 12 in Cancer Cell

In addition, 4 of 6 (67%) patients with tumors that were resistant to initial chemotherapy responded to the combination therapy, and those responses lasted, on average, for more than 6 months. 

“We were quite surprised by the responses of patients whose cancers had developed resistance to chemotherapy,” said lead researcher Anish Thomas, M.D., of NCI’s Center for Cancer Research. “Learning that these patients could stay on the combination therapy for months was the most exciting finding of the study.” 

Based on the results of the “proof-of-concept” clinical trial, two new studies have been launched.  

NCI is conducting a phase 2 randomized trial that will compare the combination therapy with topotecan alone in patients with SCLC that has relapsed. The trial includes a separate group of patients with small cell cancers that arise in organs other than the lungs, such as the bladder and cervix.  

In addition, EMD Serono, which makes berzosertib, is sponsoring a study of the combination therapy in patients with SCLC that is resistant to treatment with chemotherapy

Finding a Combination Therapy for SCLC

A goal of the current research was to identify a combination of drugs that would include topotecan but be more effective than topotecan alone. 

“In this disease, combination therapies work better than single drugs,” said Dr. Thomas. “We wanted to build on an existing standard treatment, so we set out to find a drug that could be used in combination with topotecan.” 

Chemotherapy drugs such as topotecan damage the DNA of dividing cells, which can cause the fast-growing cancer cells to die and tumors to shrink. But in some patients, chemotherapy stops working, perhaps because of the ability of tumor cells to efficiently repair DNA damage, the research team wrote. 

“Most patients with SCLC have a very good initial response to a combination of chemotherapy and immune checkpoint inhibitors,” said Dr. Thomas. “But unfortunately, the response is very transient, and in most patients the cancer comes back in 3 or 4 months.” 

When the cancer returns, it tends to be resistant to additional treatments. “We think the tumor may have an intrinsic ability to repair the DNA, which would explain the quick tumor relapses,” said Dr. Thomas.  

To find a treatment that could block the ability of tumor cells to repair damaged DNA when given in combination with topotecan, the researchers teamed up with colleagues at the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health. 

NCATS has a robotic screening technology called matrix combination screening that can rapidly assess the effects of many drugs and drug combinations on cancer cells grown in the laboratory. The results of these screens can help researchers prioritize their efforts to identify potential combination therapies, noted another researcher on the trial, Craig Thomas, Ph.D., of NCATS’s Division of Preclinical Innovation in a press release.
  
For the current study, the researchers screened several thousand possibilities. Among the most promising results was the combination of topotecan and the investigational drug berzosertib, which blocks a protein called ATR that plays an important role in DNA repair.

Blocking the ATR protein means that cancer cells cannot effectively repair the DNA damage caused by chemotherapy, noted study investigator Michele Ceribelli, Ph.D., who is also part of NCATS’s Division of Preclinical Innovation. This can potentially make chemotherapy more effective, Dr. Ceribelli added. 

Testing the Combination in Patients with Small Cell Lung Cancer

In the clinical trial involving 25 patients with SCLC, the researchers observed responses to the drug combination in patients whose tumors had responded to initial chemotherapy as well as in those whose tumors had not. 

Two of the six (33%) patients with cancers that were resistant to initial chemotherapy continued to receive the combination therapy without their cancers progressing for more than a year after starting treatment—one for 13 months and the other for 24 months.

Such lasting responses among patients with chemotherapy-resistant SCLC are notable, Dr. Thomas said, because these tumors rarely respond to treatment with topotecan alone. 

The median overall survival—the time until death—was 8.5 months, the researchers reported, noting that more than a third of the patients in the study had undergone multiple prior treatments. 

The most common side effects of the combination treatment included anemia, a lower-than-normal number of lymphocytes (a type of white blood cell), and a lower-than-normal number of platelets in the blood. 

Both drugs are given intravenously. “The sequence of administration of the two drugs is important,” said Dr. Anish Thomas. “In the laboratory we found that the most effective strategy was to give both drugs together, and the same dosing strategy was used in the clinical trial.”
   
The results need to be confirmed in a larger clinical trial, which is underway, the research team wrote.

Expanding the Trial to Include Other Small Cell Cancers

During the trial, the researchers expanded the study to include 10 patients who had small cell cancers that arose outside the lungs and got worse after initial treatment. Some of these patients also responded to the combination therapy. 

“These tumors resemble small cell cancers of the lung, and they’re just as aggressive,” said Dr. Anish Thomas.

To better understand why patients with small cell cancers of the lung or other organs did or didn’t respond to the combination therapy, the researchers analyzed the expression of certain genes in samples of their tumors collected before treatment. 

“We were able to identify a group of patients with tumors that were more likely to respond to the combination therapy,” said Dr. Thomas. “These tumors are characterized by the expression of certain genes, including genes related to rapid cell growth and repairing damaged DNA.” 

Most SCLCs are treated as though they are the same disease, but the new study suggests that the disease may include various molecular subtypes. The findings, Dr. Thomas said, “are a step toward being able to predict which patients with SCLC are most likely to benefit from certain treatments.”

Source

NEWSLETTER

Συμπληρώστε το email σας για να λαμβάνετε τις σημαντικότερες ειδήσεις από το ogkologos.com

Βρείτε μας

2,449ΥποστηρικτέςΚάντε Like
57ΑκόλουθοιΑκολουθήστε

Διαβαστε Επίσης

Καρκίνος και Κορωνοϊός (COVID-19) ΜΕΡΟΣ Α

Εάν είστε καρκινοπαθής, το ανοσοποιητικό σας σύστημα μπορεί να μην είναι τόσο ισχυρό όσο κανονικά, έτσι μπορεί να ανησυχείτε για τους κινδύνους που σχετίζονται...

ΠΑΓΚΟΣΜΙΑ ΗΜΕΡΑ ΚΑΡΚΙΝΟΥ

Η Παγκόσμια Ημέρα Κατά του Καρκίνου καθιερώθηκε με πρωτοβουλία της Διεθνούς Ένωσης κατά του Καρκίνου (UICC), που εκπροσωπεί 800 οργανώσεις σε 155 χώρες του...

ΕΞΕΛΙΞΕΙΣ ΣΤΗ ΘΕΡΑΠΕΙΑ ΤΟΥ ΜΗ-ΜΙΚΡΟΚΥΤΤΑΡΙΚΟΥ ΚΑΡΚΙΝΟΥ ΤΟΥ ΠΝΕΥΜΟΝΑ (ΜΜΚΠ)

ΕΞΕΛΙΞΕΙΣ ΣΤΗ ΘΕΡΑΠΕΙΑ ΤΟΥ ΜΗ-ΜΙΚΡΟΚΥΤΤΑΡΙΚΟΥ ΚΑΡΚΙΝΟΥ ΤΟΥ ΠΝΕΥΜΟΝΑ (ΜΜΚΠ) Γράφει ο Δρ Παπαδούρης Σάββας, Παθόλογος-Ογκολόγος   Ο ΜΜΚΠ βρίσκεται αναλογικά στο 80% και πλέον του συνολικού...

Διατρέχουν όντως οι καρκινοπαθείς μεγαλύτερο κίνδυνο λόγω κοροναϊού;

Σε πρακτικό επίπεδο, τα δεδομένα των σχετικών μελετών υποδηλώνουν ότι η χημειοθεραπεία ή οι άλλες αντι-νεοπλασματικές θεραπείες δεν αυξάνουν σημαντικά τον κίνδυνο θνησιμότητας από...

FDA: Η ακτινοβολία των smartphones δεν προκαλεί καρκίνο

Σε μια νέα έκθεσή της, η Υπηρεσία Τροφίμων και Φαρμάκων (FDA) των ΗΠΑ αναφέρει ότι επανεξέτασε τις σχετικές επιστημονικές έρευνες που δημοσιεύθηκαν τα τελευταία...

Νέα ανακάλυψη, νέα ελπίδα για τον καρκίνο

Ένα νεοανακαλυφθέν τμήμα του ανοσοποιητικού μας συστήματος θα μπορούσε να αξιοποιηθεί για την αντιμετώπιση όλων των ειδών καρκίνου, σύμφωνα με επιστήμονες του πανεπιστημίου Cardiff...
- Advertisment -

Ροή Ειδήσεων

Breast Cancer Survivor Invents Warming Bra Insert to Combat Cold Feeling of Breast Implants

In 2013, Kristen Carbone, of Providence, Rhode Island, had a preventative mastectomy to help protect herself against breast cancer after her mother died of...

FDA Approves Daratumumab plus Hyaluronidase-fihj, Carfilzomib, and Dexamethasone for Relapsed or Refractory Multiple Myeloma

On 30 November 2021, the US Food and Drug Administration (FDA) approved daratumumab plus hyaluronidase-fihj (Darzalex Faspro, Janssen Biotech, Inc.) and carfilzomib (Kyprolis, Amgen,...

Thanks For Making This GivingTuesday Our Best One Yet!

We set ambitious goals for GivingTuesday, but they were driven by a time of great need. With your help, we hoped to provide food and...

Over 600 people in England set to benefit from innovative lung cancer treatment

<img width="620" height="348" src="https://34p2k13bwwzx12bgy13rwq8p-wpengine.netdna-ssl.com/wp-content/uploads/2021/05/lung_cell_cropped-hero.jpg" class="attachment-featuredImage size-featuredImage" alt="Lung cancer cell" loading="lazy" srcset="https://34p2k13bwwzx12bgy13rwq8p-wpengine.netdna-ssl.com/wp-content/uploads/2021/05/lung_cell_cropped-hero.jpg 620w, https://34p2k13bwwzx12bgy13rwq8p-wpengine.netdna-ssl.com/wp-content/uploads/2021/05/lung_cell_cropped-hero-300x168.jpg 300w, https://34p2k13bwwzx12bgy13rwq8p-wpengine.netdna-ssl.com/wp-content/uploads/2021/05/lung_cell_cropped-hero-220x123.jpg 220w, https://34p2k13bwwzx12bgy13rwq8p-wpengine.netdna-ssl.com/wp-content/uploads/2021/05/lung_cell_cropped-hero-150x84.jpg 150w" sizes="(max-width: 620px) 100vw, 620px" data-attachment-id="18781" data-permalink="https://news.cancerresearchuk.org/2020/09/11/targeted-drug-for-lung-cancer-approved-for-nhs-use-in-england/lung_cell_cropped-hero/"...

Touching a nerve: How neuroscience could advance our understanding of cancer

KTSDESIGN/SCIENCE PHOTO LIBRARY When supporters donate to our work, their combined generosity might lead to a new discovery that inches us closer to, for example,...

Nivolumab Demonstrates Clinical Benefits in a Statistically Evaluable Number of Patients with CUP

An investigator-initiated phase II study is the first to show that nivolumab has clinical activity with manageable toxicity in a statistically evaluable number of...