Drug Resistance is one of the main reasons leading to the failure of Cancer treatment, which greatly limits the choice and use of cancer drugs, and breaking the hopes of the cancer patients again and again. The study of drug resistance in cancer is of utmost importance. It is imminent to explore the mechanism of cancer resistance and new methods to combat drug resistance.

• Insulin pathways can lead to brain tumor resistance. New discoveries bring new ideas for cancer prevention!

(DOI: 10.1158/1535-7163.MCT-16-0616)

Glioblastoma multiforme is one of the most common and highest mortality tumors. Although various advanced therapies are effective at the beginning of treatment, tumors often develop resistance and eventually recur. Recently, the team led by Dr. Damian A. Almiron Bonnin, a Ph.D. in the Mark Israel Laboratory at the Norris Cotton Cancer Research Center, has found a new way to prevent the development of anticancer drugs against brain cancer.

In this study, we successfully found a signaling pathway that led to the development of glioblastoma multiformity. Almiron Bonnin said. “More importantly, there are existing drugs that can inhibit this signaling pathway that produces resistance.”

This study found that the insulin signaling pathway plays a role in tumor growth signaling pathways in brain cancer cells treated with anticancer drugs, which leads to the tumors being able to grow while undergoing treatment. In this case, inhibiting the insulin signaling pathway can prevent tumors from developing drug resistance. This strategy may enhance the efficacy of existing anti-cancer therapies, ultimately extending the survival of this cancer patient. This work is entitled “Insulin-Mediated Signaling Facilitates Resistance to PDGFR Inhibition in Proneural hPDGFB-Driven Gliomas” and was recently published as a cover article in “Molecular Cancer Therapeutics”.

“The tumor we studied was the most common and malignant non-metastatic brain tumor in children and adults. Currently, there is no cure for this tumor,” said Almiron Bonnin. “Thus, brain cancer causes about 25% of cancer-related deaths. This kind of tumor will soon become resistant to treatment, so the effects of various existing therapies are very poor. In our lab, we try to understand what mediates drug resistance at the cellular level, so that we can develop more effective treatments. We have found a key component of the signaling pathway that leads to drug resistance, and have proposed a new strategy to solve this problem.”

Almiron Bonnin’s research will help scientists to better understand the mechanism of tumor drug resistance, which may help improve the clinical treatment of this advanced glioma. Looking ahead, the research team will develop new methods based on their new findings that may be more effective targeted therapy for this tumor.

• Cancer Cell: Molecular Mechanism of Breast Cancer Drug Resistance

(DOI: https://doi.org/10.1016/j.ccell.2018.01.004)

Recently, researchers from the Dana-Farber Cancer Institute have discovered the molecular mechanisms by which ER-positive Breast Cancer cells develop resistance and deterioration to conventional therapies. Scientists say the study explains why breast cancer cells with ER mutations develop drug resistance and become more prone to worsening after receiving aromatase inhibitors and tamoxifen treatment. At present, drug resistance of ER-positive breast cancer is a clinically urgent problem to be solved.

Cancer cells in most breast cancer patients rely on estrogen for survival. Most drugs suppress the growth of cancer by blocking the production of estrogen or blocking the estrogen receptor in cancer cells. This endocrine therapy, including tamoxifen and aromatase inhibitor drugs, can inhibit the recurrence of early breast cancer and can also delay the development of malignant cancer. However, one-third of ER-positive breast cancer patients still relapse after receiving the above-mentioned drug treatment, and relapsed cancer cells can grow without estrogen, thus resulting in the emergence of drug resistance.

In this study, the authors found that three of the ER gene mutations previously unknown effects. These mutations not only lead to the tumor survival in the absence of estrogen, but also can initiate the expression of other genes, thereby promoting tumor progression and metastasis.

Using the CRISPR-Cas9 gene editing tool, the authors identified genes that are important for ER mutations. Of these important genes, CDK7 is particularly valued by researchers because of a potential drug target. In fact, Dr. Nathanael Gray and others had previously developed the experimental CDK7 inhibitor THZ1. The results of studies at the cellular level and at the animal model level indicate that the combined use of THZ1 and the endocrine inhibitor fulvestrant can delay the growth of the tumor, and its effect is significantly stronger than the use of the aforementioned drugs alone.

“These results show that combined drug therapy can solve the problem of drug resistance in ER-positive breast cancer,” the authors said.

• Nat Commun: Scientists Make Breakthrough Progress in Overcoming Tumor Multidrug Resistance

(DOI: 10.1038/s41467-018-02915-8)

Cancer cell resistance to chemotherapy – commonly known as multidrug resistance – remains the leading cause of tumor recurrence and cancer metastasis, but recent findings have raised hopes for oncologists who may direct tumor cells turn off their resistance in the future.

New research by Xiaoming He, professor of the Fisher Biotechnology Department at the University of Maryland College Park, and researchers from five other research institutes has developed a new technology that can use specially designed nanoparticles and near-infrared light treatment to lead tumor cells lose drug resistance. This creates a method for chemotherapy to treat the most resistant cancer cells left behind of surgery or early treatment. Their new discovery was recently published in Nature Communications.

“If chemotherapy is performed within this treatment window, oncologists may be able to use a very low dose of chemotherapeutic drugs for cancer treatment, which will help improve the efficacy of the treatment and reduce the toxicity of chemotherapy drugs to normal tissues,” said He. One of the main reasons for the development of drug resistance in tumor cells is the overexpression of drug efflux pumps. They are proteins that can protect cells and can pump unwanted toxic substances out of the cells. Just as efflux pumps can remove toxins from cells to protect cells, they also pump almost all clinically used chemotherapeutic drugs out of the cell.

Fortunately, efflux pumps require chemical energy to work. Therefore, by cutting off the energy source of the efflux pump, oncologists can reduce or even eliminate cell resistance to chemotherapeutic drugs. Recognizing this, He and his colleagues developed a new method to reduce the amount of adenosine triphosphate (ATP) that supplies efflux pumps in cancer cells.

The research team includes researchers from Ohio State University, the University of Virginia, the University of Missouri School of Medicine, Shanghai University of Traditional Chinese Medicine, and Indiana University School of Medicine. They targeted a specially designed nanoparticle to the mitochondria. The mitochondria are the energy supply station that oxygen and energy are transformed into an ATP in the cell. Once the nanoparticles reached the mitochondria, the researchers used near-infrared light to cause the nanoparticles to chemically consume ATP, thereby reducing their concentration and cutting off the energy supply of the efflux pump. This treatment not only reduces the expression of the efflux pump, but also reduces their distribution in the cell membrane.

The team’s findings indicate that the use of drug-loaded nanoparticles in combination with near-infrared light can effectively inhibit the growth of multidrug resistant cells without significant systemic toxicity. Although researchers used nanoparticle delivery drugs long ago, the method proposed by He and colleagues is still a key breakthrough in overcoming multidrug resistance of cancer cells.

“For many years researchers have focused on using nanoparticles to deliver more chemotherapeutic drugs into cancer cells, but there is no source of targeted resistance,” He said. “This means that cancer cells will continue to maintain their ability to expel drugs out of the cell, which limits the effectiveness of chemotherapy. To address this challenge, our team not only uses nanoparticles to deliver chemotherapy drugs to target sites within tumor cells, it also inhibits the function of the efflux pump, thereby significantly improving the safety and efficacy of chemotherapy.”

• Ann Oncol: Overcoming resistance to breast cancer will not be a dream! Researchers have discovered mutations that lead to ER+ breast cancer resistance!

(DOI:https://doi.org/10.1093/annonc/mdy025)

At the Magi Institute of Gynaecology (MWRI) and the UPMC Hillman Cancer Research Center at the University of Pittsburgh, USA, a large group of clinicians and researchers working on the most common mechanisms of breast cancer resistance have discovered a new mutation of estrogen receptor (ER) will lead to drug resistance. ER+ breast cancer accounts for two-thirds of breast cancer cases, and grows by estrogen supplying energy. Anti-estrogen therapy is usually effective at the beginning of treatment, but ER+ breast cancer usually recurs due to tumor resistance.

In a study published in the Annals of Oncology, the researchers found that the ER gene ESR1 fusion protein appeared in drug-resistant tumor tissues. This is the first time that ESR1 fusion proteins have been found in human breast cancer tissues. Exploring how they function will improve the treatment of this cancer.

“We found this change in a patient with ER+ breast cancer who received anti-estrogen therapy and died of relapse.” Corresponding Author, MWRI and UMC Hillman Cancer Research Center Director of the Women’s Cancer Research Center, University of Pittsburgh Pharmacy and Chemistry Biology professor Dr. Adrian Lee said. “A member of our lab took note of this mutation in the tissue genetic analysis. Over time, we discovered this mutation in many relapsed patients.” The work was carried out by them in collaboration with gene sequencing company Foundation Medicine Inc. The company used their FoundationOne CDx test to detect ESR1 fusion in nearly 10,000 breast cancer patients.

According to Lee, the ESR1 fusion protein can break down to one-half the original and clear the anti-estrogen therapy targeted binding sites to avoid this treatment. “The doctor will continue to give the patient anti-estrogen treatment, but did not realize that this gene mutation has occurred,” said Lee. “Now we know about this change. We can detect this mutation through blood tests, which will help improve the status of the treatment of this type of tumor.”

“Gene sequencing is telling us more about breast cancer. I believe our research will have a huge impact on clinical practice in the near future. Our work will bring hope for improving patient care and survival.”

(To be continued…)

Reference

Damian A. et al. Insulin-Mediated Signaling Facilitates Resistance to PDGFR Inhibition in Proneural hPDGFB-Driven Gliomas. Mol Cancer Ther, 2017 Apr;16(4):705-716. doi: 10.1158/1535-7163.MCT-16-0616.

Jeselsohn R. et al. Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations. Cancer Cell. 2018 Feb 12;33(2):173-186.e5. doi: 10.1016/j.ccell.2018.01.004.

Wang H. et al. Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance. Nat Commun. 2018 Feb 8;9(1):562. doi: 10.1038/s41467-018-02915-8.

Hartmaier RJ. et al. Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer. Ann Oncol. 2018 Apr 1;29(4):872-880. doi: 10.1093/annonc/mdy025.