Tagged: Chemotherapy

Trending With Impact: Low-Dose Chemo Inhibits Resistant Breast Cancer

In this trending in vitro study, researchers assessed the efficacy of low-dose 6-mercaptopurine and 5-azacitidine to inhibit high resistance triple-negative breast cancer cells.

Photomicrograph of a breast cancer (grade 3 invasive ductal carcinoma) with frequent mitoses (mitotic figures), including a large central atypical mitoses.
Photomicrograph of a breast cancer (grade 3 invasive ductal carcinoma) with frequent mitoses (mitotic figures), including a large central atypical mitoses.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Triple-negative breast cancer (TNBC) accounts for 10-15% of all breast cancers. “Triple-negative” in this subtype of breast cancer cell refers to the lack of HER2 protein and estrogen and progesterone receptors. This means that TNBC cannot be treated with hormone inhibition and must be treated with conventional chemotherapy. In addition, many of these breast cancer cells can opportunistically switch between proliferation and quiescence—a difficult phenotype to treat. Patients diagnosed with this highly adaptable cancer frequently relapse and develop resistance to treatments.

In 2021, researchers from The University of Texas MD Anderson Cancer Center conducted a research study in hopes of developing a safe and effective therapeutic combination to treat resistant triple-negative breast cancer. Their paper, published in Oncotarget’s Volume 12, Issue 7, was entitled: “Inhibition of resistant triple-negative breast cancer cells with low-dose 6-mercaptopurine and 5-azacitidine.” 

The Study

“Evidence suggests that SUM149-metabolic adaptable (MA) cells are a suitable model of resistant human triple-negative breast cancer (TNBC) cells that can survive bottlenecks in the body, including therapeutic interventions, by opportunistically switching between quiescence and cell proliferation [578].”

In this in vitro study, researchers cultured three highly drug-resistant and metastatic progenitor-like TNBC cell lines with opportunistic switching between quiescence and proliferation. Researchers focused on designing a safe treatment that is effective in both low- and high-risk patients. The researchers note that it was critical to their study that the regimen is proven safe to administer to patients for early use in the minimal residual disease (MRD) stage after surgery, and before clinical metastasis is detected.

“For a potential therapy to be suitable at the MRD stage, it must be safe (an important criterion prior to clinical relapse) and disrupt heterogeneous progenitor-like cancer cells that evolve into clinical metastases.”

Two chemotherapy and immunosuppressive drugs (ribonucleoside analogues) were tested on the cell lines at low doses for the sake of viability in the MRD stage: 6-mercaptopurine (6-MP) and 5-azacitidine (5-AzaC). Both of these drugs have been clinically proven to be well-tolerated and to have drug-sensitizing, quiescence-stabilizing, and apoptosis-inducing effects in cancer cells.

“We chose 5-AzaC because it could complement 6-MP’s effects on the transcriptome and epigenome, and—as indicated by many Phase 1 clinical trials—5-AzaC is well tolerated [11].”

Results & Conclusion

“Our studies suggest that low-dose 6-MP, which is a purine analogue and very effective in maintaining remission in IBD [9], inhibits highly adaptable TNBC cells in our model, presumably by disrupting their transcriptome and epigenome.”

Researchers found that these low-dose therapeutics take several weeks to become effective. Despite the low dose, 6-MP (complimented by 5-AzaC) was capable of inhibiting highly adaptable TNBC cells. The researchers also point out that, based on decades of 6-MP’s use in patients with inflammatory bowel disease (IBD), this drug may be used regularly to modulate the immune system and prevent disease recurrence through its ability to inhibit chronic inflammation associated with advanced cancers.

“We suggest that low dose 6-MP and other drugs that would complement 6-MP’s action, such as 5-AzaC, could be suitable for preventing recurrence and metastasis in high-risk breast cancers. 6-MP could be taken lifelong if it is necessary for maintaining a long-term remission.”

Click here to read the full scientific study, published by Oncotarget.

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Trending with Impact: Nimotuzumab Improves Non-HPV Oropharynx Cancers

Researchers perform a subgroup analysis study demonstrating positive results in patients with HPV-negative oropharyngeal cancers due to the addition of nimotuzumab while receiving cisplatin and radiation treatment.

An image depicting the nasopharynx, pharynx, and the oropharynx.
An image depicting the nasopharynx, pharynx, and the oropharynx.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news and articles about the latest trending publications here, and at Oncotarget.com.

Oral cancer in any part of the oropharynx (the back-third of the tongue, tonsils, soft palate, and back and sides of the throat) is called oropharyngeal cancer. Each year, oral cancer accounts for around 53,000 new patient diagnoses in the United States. However, the highest number of cases of oral cancer in the world are found in India, and this number is increasing.

“As opposed to HPV related oropharyngeal cancer, HPV negative oropharyngeal cancers have worse prognosis.”

Researchers from Tata Memorial Hospital and Tata Memorial Centre in Mumbai, India, previously reported that in a phase three randomized study of an epidermal growth factor receptor inhibitor medication and, called cetuximab, showed a trend towards improvement when used in patients with locally advanced head and neck cancers. Compared with results in other similar studies, they believe their results were likely due to a younger cohort of patients with predominantly HPV negative diseases.

“Taking this into consideration, we decided to perform a subgroup analysis of the HPV negative oropharyngeal cancer cohort, to study the absolute improvement in 2-year outcomes with the addition of nimotuzumab. We compared 2 year progression free survival (PFS), disease free survival (DFS), locoregional control (LRC) and overall survival (OS) between both arms.”

The Study

“HPV negative oropharyngeal cancer has unsatisfactory treatment outcomes and is a candidate for escalation of treatment. We wanted to determine whether the addition of nimotuzumab to cisplatin-radiation could improve outcomes in these poor-risk tumors.”

In this study, the researchers gathered 536 patients undergoing definitive chemoradiation for locally advanced head and neck cancers, with 269 having a primary tumor located in the oropharynx. Of these patients, 187 were p16 protein negative and were divided into two treatment arms: 91 in the cisplatin-radiotherapy (CRT) treatment arm and 97 in the nimotuzumab-cisplatin-radiotherapy (NCRT) treatment arm. Nimotuzumab is an antibody that binds to epidermal growth factor receptor IgG1 and a radiosensitizer.

The cohort consisted of only 21 females, therefore the participants were primarily male, with a median age of 54.5, 90% reported tobacco use, and 80% were in disease stage IV. Patients in the CRT treatment arm were given 30mg/m2 of cisplatin weekly, in addition to radiation therapy. In the NCRT treatment arm, in addition to radiation therapy, patients received 200 mg of nimotuzumab and 30 mg/m2 cisplatin weekly. 

Results

Researchers found that the HPV positive/negative interaction test using immunohistochemistry staining taken by each participant was a significant determinant in progression free survival, locoregional control, and overall survival, but not in disease free survival. They suggest this data shows that the addition of nimotuzumab has a differential patient impact on disease free survival with respect to HPV status.

In patients taking nimotuzumab, improvement in locoregional control was largely responsible for their improvement in progression free survival. On average, time to locoregional failure in the CRT treatment arm was 17.3 months, and in the NCRT treatment arm, it was 60.3 months. The team also found that the addition of nimotuzumab led to an 18.6% improvement in 2-year overall survival, jumping from 39.0% to 57.6%.

Figure 4: Restricted mean overall survival plots of both arms. arm = 0 represents the plot of the cisplatin radiotherapy arm while arm = 1 represents the plot of the Nimotuzumab-cisplatin radiotherapy arm.
Figure 4: Restricted mean overall survival plots of both arms. arm = 0 represents the plot of the cisplatin radiotherapy arm while arm = 1 represents the plot of the Nimotuzumab-cisplatin radiotherapy arm.

“Locoregional control, progression-free survival and overall survival were improved with the addition of nimotuzumab to cisplatin and radiation.”

Conclusion

“The addition of nimotuzumab to weekly cisplatin-radiation improves outcomes inclusive of OS in HPV negative oropharyngeal cancers.”

“The results of the current study clarify the importance of treatment intensification in HPV negative oropharyngeal cancers.”

Click here to read the full scientific study, published in Oncotarget.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.