Novel and unique DNA vaccine to fight effectively against cancer antigen

Scientists at The Wistar Institute and Inovio pharmaceuticals, Inc. have devised a unique deoxyribonucleic acid (DNA) vaccine approach through molecular design to boost the immune responses induced against one of the most important cancer antigen targets. Research results were published in the journal Molecular Therapy.

Cancer immunotherapy approaches, designed to harness the body’s natural immune defenses to focus on and kill cancer cells, are showing great promise for cancer treatment and prevention. DNA vaccines can induce immunity through the delivery by an intramuscular injection of a sequence of synthetically designed DNA that contains the instructions for the immune cells in the body to become activated and target a particular antigen against which an immunologic response is wanted.

Despite being specific for cancer cells, cancer tumor-associated antigens generally trigger weak immune responses as a result of they’re recognized as self-antigens and also the body has in place natural mechanisms of immune acceptance, or “Tolerance”, that forestall autoimmunity and also additionally limit the efficacy of cancer vaccines. This is often the case of Wilm’s tumor gene 1 (WT1), a cancer tumor antigen that’s overexpressed in many varieties of cancer and possibly plays a key role in driving tumor development. vaccine approaches against WT1 thus far haven’t appeared promising because of immune tolerance leading to poor immune responses against cancers expressing WT1.

Wistar scientists have developed a unique WT1 deoxyribonucleic acid (DNA) vaccine employing a strategically changed DNA sequence that tags the WT1 as foreign to the host immune system breaking tolerance in animal models.

“This is an important time in the development of anti-DNA cancer immune therapy approaches. This team has developed an approach that may play an important role in generating improved immunity to WT1 expressing cancers,”said David B. Weiner, Ph.D., Executive Vice President and Director of the Vaccine Center at The Wistar Institute and the W.W. Smith Charitable Trust Professor in Cancer Research, and senior author of the study.”These immune responses represent a unique tool for potentially treating patients with multiple forms of cancer. Our vaccine also provides an opportunity to combine this approach with another immune therapy approach, checkpoint inhibitors, to maximize possible immune therapy impact on specific cancers.”

The team lead by Weiner has optimized the dna vaccine employing a artificial dna sequence for WT1 that, while maintaining a very high similarity with the native sequence, contains new modified sequences that differ from native WT1 in an attempt to render it more recognizable by the host immune system. The novel WT1 vaccine was superior to a more traditional native WT1 vaccine because it was able to break immune tolerance and induce long-term immune memory. Significantly, the vaccine also stimulated a therapeutic anti-tumor response against leukemia in mice.

Citation: Walters, Jewell N., Bernadette Ferraro, Elizabeth K. Duperret, Kimberly A. Kraynyak, Jaemi Chu, Ashley Saint-Fleur, Jian Yan, Hy Levitsky, Amir S. Khan, Niranjan Y. Sardesai, and David B. Weiner. “A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity.” Molecular Therapy, 2017. doi:10.1016/j.ymthe.2017.01.022.
Research funding: Inovio Pharmaceuticals, Inc. Basser Center for BRCA/Abramson Cancer CenterWeiner, W.W. Smith Charitable Trust Professorship for Cancer Research.
Adapted from press release by The Wistar Institute.

Role of Vitamin C in cancer treatment

Vitamin C has a patchy history as a cancer therapy, but researchers at the University of Iowa believe that is because it has often been used in a way that guarantees failure. Most vitamin C therapies involve taking the substance orally. However, the UI scientists have shown that giving vitamin C intravenously and bypassing normal gut metabolism and excretion pathways create blood levels that are 100 – 500 times higher than levels seen with oral ingestion. It is this super-high concentration in the blood that is crucial to vitamin C’s ability to attack cancer cells.

Citrus fruits, a rich source of Vitamin C. Credit: LoggaWiggler/pixabay

Earlier work by UI redox biology expert Garry Buettner found that at these extremely high levels (in the millimolar range), vitamin C selectively kills cancer cells but not normal cells in the test tube and in mice. Physicians at UI Hospitals and Clinics are now testing the approach in clinical trials for pancreatic cancer and lung cancer that combine high-dose, intravenous vitamin C with standard chemotherapy or radiation. Earlier phase 1 trials indicated this treatment is safe and well-tolerated and hinted that the therapy improves patient outcomes. The current, larger trials aim to determine if the treatment improves survival.

In a study, published in journal Redox Biology, Buettner and his colleagues have homed in on the biological details of how high-dose vitamin C (also known as ascorbate) kills cancer cells. The study shows that vitamin C breaks down easily, generating hydrogen peroxide, a so-called reactive oxygen species that can damage tissue and DNA. The study also shows that tumor cells are much less capable of removing the damaging hydrogen peroxide than normal cells.

“In this paper we demonstrate that cancer cells are much less efficient in removing hydrogen peroxide than normal cells. Thus, cancer cells are much more prone to damage and death from a high amount of hydrogen peroxide,” says Buettner, a professor of radiation oncology and a member of Holden Comprehensive Cancer Center at the University of Iowa. “This explains how the very, very high levels of vitamin C used in our clinical trials do not affect normal tissue, but can be damaging to tumor tissue.”

Normal cells have several ways to remove hydrogen peroxide, keeping it at very low levels so it does not cause damage. The new study shows that an enzyme called catalase is the central route for removing hydrogen peroxide generated by decomposing vitamin C. The researchers discovered that cells with lower amounts of catalase activity were more susceptible to damage and death when they were exposed to high amounts of vitamin C.

Buettner says this fundamental information might help determine which cancers and which therapies could be improved by inclusion of high-dose ascorbate in the treatment. “Our results suggest that cancers with low levels of catalase are likely to be the most responsive to high-dose vitamin C therapy, whereas cancers with relatively high levels of catalase may be the least responsive,” he explains. A future goal of the research is to develop methods to measure catalase levels in tumors.

Citation: Doskey, Claire M., Visarut Buranasudja, Brett A. Wagner, Justin G. Wilkes, Juan Du, Joseph J. Cullen, and Garry R. Buettner. “Tumor cells have decreased ability to metabolize H 2 O 2: Implications for pharmacological ascorbate in cancer therapy.” Redox Biology 10 (2016): 274-284.
DOI: 10.1016/j.redox.2016.10.010
Research Funding: National Institutes of Health, Gateway for Cancer Research.
Adapted from press release by the University of Iowa.

Piperlongumine, chemical from Indian pepper plant inhibits enzyme in cancer cells

UT Southwestern Medical Center scientists have uncovered the chemical process behind anti-cancer properties of a spicy Indian pepper plant called the long pepper, whose suspected medicinal properties date back thousands of years. The study is published in the Journal of Biological Chemistry.

Dr. Westover’s lab used X-ray crystallography to create this molecular model of piperlongumine.
Credit: UT Southwestern

The secret lies in a chemical called Piperlongumine (PL), which has shown activity against many cancers including prostate, breast, lung, colon, lymphoma, leukemia, primary brain tumors, and gastric cancer.

Using x-ray crystallography, researchers were able to create molecular structures that show how the chemical is transformed after being ingested. Piperlongumine (PL) converts to hPiperlongumine (hPL), an active drug that silences a gene called GSTP1. The GSTP1 gene produces a detoxification enzyme Glutathione S-Transferase Pi 1 that is often overly abundant in tumors.

“We are hopeful that our structure will enable additional drug development efforts to improve the potency of PL for use in a wide range of cancer therapies,” said Dr. Kenneth Westover, Assistant Professor of Biochemistry and Radiation Oncology. “This research is a spectacular demonstration of the power of x-ray crystallography.”

Dr. Westover, a member of the Harold C. Simmons Comprehensive Cancer Center, used cutting edge technologies in UT Southwestern’s Structural Biology Core (SBC) – the University’s world-renowned facility for X-ray crystallography, to better understand the anticancer properties of Piperlongumine (PL). X-ray crystallography allows scientists to determine molecular structures that reveal how molecules interact with targets – in this case how Piperlongumine (PL) interacts with GSTP1. Viewing the structures helps in developing drugs for those targets.

Citation: Harshbarger, Wayne, Sudershan Gondi, Scott B. Ficarro, John Hunter, Durga Udayakumar, Deepak Gurbani, William Singer, Yan Liu, Lianbo Li, Jarrod A. Marto and Kenneth D. Westover. “Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine.” Journal of Biological Chemistry (2016): jbc-M116.
DOI: 10.1074/jbc.M116.750299
Research funding: V Foundation for Cancer Research, Welch Foundation, and Cancer Prevention and Research Institute of Texas.
Adapted from press release by UT Southwestern Medical Center.

Capsaicin, an active ingredient of chili peppers found to inhibit breast cancer cells in vitro

Capsaicin, an active ingredient of pungent substances such as chili or pepper, inhibits the growth of breast cancer cells. This was reported by a team headed by the Bochum-based scent researcher  Prof. Dr. Dr. Dr. med. habil. Hanns Hatt and Dr. Lea Weber, following experiments in cultivated tumor cells. The study was published in the journal “Breast Cancer – Targets and Therapy”.

The experiments were carried out with the SUM149PT cell culture, a model system for a particularly aggressive type of breast cancer, i.e. the triple-negative type. Chemotherapy is currently the only available treatment for this type of cancer.

In the cultivated cells, the team detected a number of typical olfactory receptors. One receptor occurred very frequently; it is usually found in the fifth cranial nerve, i.e. the trigeminal nerve. It belongs to the so-called Transient Receptor Potential Channels and is named TRPV1. That receptor is activated by the spicy molecule capsaicin as well as by helional – a scent of fresh sea breeze.

In collaboration with Dr. Gabriele Bonatz from the Augusta clinics in Bochum (Brustzentrum), Hatt’s team confirmed the existence of TRPV1 in tumor cells in nine different samples from patients suffering from breast cancer.

The researchers activated the TRPV1 receptor in the cell culture with capsaicin or helional, by adding the substances to the culture for a period of several hours or days. As a result, the cancer cells divided more slowly. Moreover, the treatment caused tumour cells to die in larger numbers. The surviving cells were no longer able to move as quickly as heretofore; this implies that their ability to form metastases in the body was impeded.

“If we could switch on the TRPV1 receptor with specific drugs, this might constitute a new treatment approach for this type of cancer,” says Hanns Hatt. An intake via food or inhalation is insufficient for this purpose.

Earlier studies had demonstrated that the chemical arvanil – with a chemical make-up similar to that of the spicy molecule capsaicin – was effective against brain tumours in mice; it reduces tumour growth in the animals. Due to its side effects, however, this substance is not approved for humans. In addition to capsaicin and helional, the endovanilloids, produced naturally in the body, also activate the TRPV1 receptor.

Citation: Weber, Lea V, Klaudia Al-Refae, Gerhard Wölk, Gabriele Bonatz, Janine Altmüller, Christian Becker, Günter Gisselmann & Hanns Hatt. “Expression and functionality of TRPV1 in breast cancer cells”. Breast Cancer: Targets and Therapy 2016 vol: Volume 8 pp: 243-252.
DOI: 10.2147/BCTT.S121610
Research funding:  Heinrich-und-Alma-Vogelsang-Stiftung, German Research Foundation.
Adapted from press release by Ruhr-Universitaet-Bochum.

Calcium channel blockers used for hypertension has potential to block cancer invasion

By screening already approved drugs, the team led by Postdoctoral Researcher Guillaume Jacquemet and Academy Professor Johanna Ivaska has discovered that calcium channel blockers can efficiently stop cancer cell invasion in vitro. Calcium channel blockers are currently used to treat hypertension, also known as high blood pressure, but their potential use in blocking cancer cell metastases has not been previously reported.

High-resolution microscope image of an invasive breast cancer cell (magenta) expressing
Myosin-10 induced “sticky-fingers” (green). Credit: Dr Guillaume Jacquemet, University of Turku.

Cancer kills because of its ability to spread throughout the body and form metastases. Therefore, developing drugs that block the ability of cancer cells to disseminate is a major anti-cancer therapeutic avenue. Developing new drugs, however, is a very lengthy and expensive process and many promising drugs fail clinical trials because of unanticipated toxicity and side effects. Thus, finding new targets for drugs already in use to treat other diseases, in other words, drug repurposing, is an emerging area in developing anti-cancer therapies.

Identification of anti-hypertension drugs as potential therapeutics against breast and pancreatic cancer metastasis was a big surprise. The targets of these drugs were not known to be present in cancer cells and therefore no one had considered the possibility that these drugs might be effective against aggressive cancer types, says Professor Ivaska.

For several years, the research team from the Turku Centre for Biotechnology lead by Professor Johanna Ivaska has focused their efforts on understanding how cancer cells move and invade surrounding tissue. The team has identified that aggressively spreading cancer cells express a protein called Myosin-10 which drives cancer cell motility.

Myosin-10 expressing cancers have a large number of structures called filopodia. They are sticky finger-like structures the cancer cells extend to sense their environment and to navigate – imagine a walking blind spider, explains Dr. Jacquemet.

The team found that calcium channel blockers target specifically these sticky fingers rendering them inactive, thus efficiently blocking cancer cell movement. This suggests that they might be effective drugs against cancer metastasis. However, at this stage, much more work is required to assess if these drugs would be efficient against cancer progression.

The team and their collaborators are currently assessing the efficiency of calcium channel blockers to stop the spreading of breast and pancreatic cancer using pre-clinical models and analyzing patient data. The findings were published in Nature Communications journal.

Citation: Jacquemet, Guillaume, Habib Baghirov, Maria Georgiadou, Harri Sihto, Emilia Peuhu, Pierre Cettour-Janet, Tao He, Merja Perälä, Pauliina Kronqvist, Heikki Joensuu & Johanna Ivaska. “L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling.” Nature Communications 7 (2016): 13297.
DOI:10.1038/ncomms13297
Adapted from press release by the University of Turku.

New approach to targeted cancer treatment and imaging by utilizing glycosidase activation of glyconaphthalimides.

Scientists from Trinity College Dublin have uncovered a new class of compounds glyconaphthalimides that can be used to target cancer cells with greater specificity than current options allow. The study was published in the journal Chemical Communications.

Cervical cancer cells show green fluorescence from enzyme-activated compound.
Credit: Eoin Scanlan, Trinity College Dublin.

Cancer is difficult to treat, and many current therapies are unable to specifically target cancer cells. This is problematic for medical professionals and patients, because it limits the dose of the drug that can be safely administered, and often causes severe and debilitating side-effects.

But the Trinity scientists have now demonstrated that a class of naturally occurring enzymes  glycosidases  that are heavily overexpressed in tumor tissue can be used to trigger the release of therapeutic payloads only in the local tumor sites where they are needed.

This finding may therefore result in the development of improved targeted cancer therapies with significantly reduced side-effects for patients.

In addition to killing cancer cells, the technology may also be used to image cancer cells, with potential applications in cancer imaging and diagnosis.

Associate Professor in Chemistry at Trinity, Eoin Scanlan, led the multidisciplinary group. He said: “This is a really exciting discovery because it brings us closer to more targeted treatment of cancer. Some current therapies are limited due to the toxicity of the compounds, but our compounds are completely inactive until they are released by the enzymes that are naturally overexpressed at the tumour site. The active compound is then rapidly taken up by cancer cells.”

“Our next steps will be to apply this technology to release specific anti-cancer drugs and to test it against a range of different cancer types.”

Citation: Calatrava-Pérez, Elena, Sandra A. Bright, Stefan Achermann, Claire Moylan, Mathias O. Senge, Emma B. Veale, D. Clive Williams, Thorfinnur Gunnlaugsson, and Eoin M. Scanlan. “Glycosidase activated release of fluorescent 1, 8-naphthalimide probes for tumor cell imaging from glycosylated ‘pro-probes’.” Chemical Communications 52, no. 89 (2016): 13086-13089.
DOI: 10.1039/C6CC06451E 
Research funding: Science Foundation Ireland.
Adapted from press release by Trinity College Dublin.

Trastuzumab biosimilar (MYL-14010) shown effective in breast cancer clinical trial

Among women with metastatic breast cancer, treatment with a drug that is biosimilar to the breast cancer drug trastuzumab resulted in an equivalent overall response rate at 24 weeks compared with trastuzumab, according to a study published online by JAMA.

Trstuzumab Biosimilars
Biological agents, including monoclonal antibodies, have increased the treatment options and greatly improved outcomes for a number of cancers. However, patient access to these biologics is limited in many countries. With impending patent expiration of some biological agents, development of biosimilars has become a high priority for drug developers and health authorities throughout the world to provide access to high-quality alternatives. A biosimilar drug is a biological product that is highly similar to a licensed biological product, with no clinically meaningful differences in terms of safety or potency.

Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves progression-free and overall survival in patients with ERBB2 (HER2)-positive metastatic breast cancer. In this multicenter, phase 3 study, Hope S. Rugo, M.D., of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and colleagues randomly assigned patients with ERBB2-positive metastatic breast cancer to receive a proposed trastuzumab biosimilar (MYL-14010) (n = 230) or trastuzumab (n = 228) with a taxane (a chemotherapy agent) to compare the overall response rate and safety after 24 weeks. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred. Tumor was assessed every 6 weeks. The primary outcome was week 24 overall response rate defined as complete or partial response.

The overall response rate was 70 percent for the proposed biosimilar vs 64 percent for trastuzumab. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41 percent vs 43 percent), progression-free survival (44 percent vs 45 percent), or overall survival (89 percent vs 85 percent). In the proposed biosimilar and trastuzumab groups, 99 percent and 95 percent of patients had at least 1 adverse event.

“Trastuzumab is not widely available around the world,” the authors write. “A biosimilar treatment option may increase global access to biologic cancer therapies, provided, among other issues, that the price of the biosimilar is sufficiently inexpensive to enable women in non-high-income countries to access this therapy.”

The researchers note that further study is needed to assess safety as well as long-term clinical outcome.

Additional Comments
With trastuzumab coming towards end of its patent life we should expect arrival of new biosimilar drugs that will mimic transtuzumab in action and potency. It is a good news to see some of them in action such as above. There is a new hope with arrival of these biosimilar drugs that it will be widely available around the world at reasonable price level.

Citations
1.“Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)–Positive Metastatic Breast Cancer: A Randomized Clinical Trial”. Hope S. Rugo, Abhijit Barve, Cornelius F. Waller, Miguel Hernandez-Bronchud, Jay Herson, Jinyu Yuan, Rajiv Sharma, Mark Baczkowski, Mudgal Kothekar, Subramanian Loganathan, Alexey Manikhas, Igor Bondarenko, Guzel Mukhametshina, Gia Nemsadze, Joseph D. Parra, Maria Luisa T. Abesamis-Tiambeng, Kakhaber Baramidze, Charuwan Akewanlop, Ihor Vynnychenko, Virote Sriuranpong, Gopichand Mamillapalli, Sirshendu Ray, Eduardo P. Yanez Ruiz, Eduardo Pennella. JAMA vol: 56 (4) pp: 226-243.
DOI: 10.1001/jama.2016.18305
Research funding: Mylan Inc., Biocon Research Limited.
Adapted from press release by The JAMA Network.

Liquid biopsies for lung cancer could predict best treatment

A blood test could predict how well small-cell lung cancer (SCLC) patients will respond to treatment, according to new research published in Nature Medicine today. Scientists, based at the Cancer Research UK Manchester Institute at The University of Manchester, isolated tumor cells that had broken away from main cancer known as circulating tumor cells (CTCs) – from the blood of 31 patients with this aggressive form of the disease. When researchers analyzed these cells, they discovered that patterns of genetic faults measured before treatment were linked to how well and how long a patient might respond to chemotherapy.

Obtaining a tumor sample from lung cancer patients using an operation, known as a biopsy, can be difficult because the tumor is hard to reach and samples are often too small to reveal useful clues on how best to treat patients. Liquid biopsies offer an alternative to taking tumor samples, providing a snapshot of the disease from a blood sample.

The team also investigated the genetic changes that occurred in patients who initially responded well to treatment but later relapsed. The pattern in these cells was different from patients who didn’t respond well to chemotherapy, suggesting different mechanisms of drug resistance had developed.

Lead researcher Professor Caroline Dive, based at the Cancer Research UK Manchester Institute, said: “Our study reveals how blood samples could be used to anticipate how lung cancer patients may respond to treatments”. Unfortunately, we have very few treatment options for patients with SCLC and none at all for those whose cancer is resistant to chemotherapy. “By identifying differences in the patterns of genetic faults between patients, we now have a starting point to begin to understand more about how drug resistance develops in patients with this aggressive form of lung cancer.”

Dr. Emma Smith, Cancer Research UK’s science information manager, said: “Lung cancer causes more than one in five of all cancer deaths in the UK and it’s vital that we find effective new treatments to fight the disease and save more lives. “These liquid biopsies are an incredibly exciting area of research. Studies like this help build a bigger picture of the disease, pointing the way to developing new treatments that are urgently needed for people with lung cancer.”

Citation: “Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer”. Louise Carter, Dominic G Rothwell, Barbara Mesquita, Christopher Smowton, Hui Sun Leong, Fabiola Fernandez-Gutierrez, Yaoyong Li, Deborah J Burt, Jenny Antonello, Christopher J Morrow, Cassandra L Hodgkinson, Karen Morris, Lynsey Priest, Mathew Carter, Crispin Miller, Andrew Hughes, Fiona Blackhall, Caroline Dive & Ged Brady. Nature Medicine 2016.
DOI: http://dx.doi.org/10.1038/nm.4239
Adapted from press release by the University of Manchester.

Arecoline, stimulant from areca nut found to have anticancer properties

Researchers at Winship Cancer Institute of Emory University have discovered  that Arecoline, the stimulant component of areca nuts has anticancer properties. The findings are scheduled for publication in Molecular Cell.

This is a ripe areca nut and the the chemical structure of arecoline

Areca nuts are chewed for their stimulant effects in many Asian countries, and evidence links the practice to the development of oral and esophageal cancer. Analogous to nicotine, arecoline was identified as an inhibitor of the enzyme ACAT1, which contributes to the metabolism-distorting Warburg effect in cancer cells.

Jing Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute says that arecoline could be compared to arsenic, a form of which is used as a treatment for acute promyelocytic leukemia, but is also linked to several types of cancer. Plus, arecoline’s cancer-promoting effects may be limited if it is not delivered or absorbed orally, he says.

The Warburg effect, named after 1931 Nobel laureate Otto Warburg, describes how cancer cells tend to favor the inefficient use of glucose, known as glycolysis, and de-emphasize their mitochondria. Cancer cells benefit from this metabolic distortion because the byproducts of glycolysis can be used as building blocks for fast growth.

Chen’s laboratory had previously identified the mitochondrial thiolase ACAT1 (acetyl-CoA acetyltransferase) as a control valve regulating the Warburg effect. In this paper, the researchers showed that ACAT1 enzymatic activity was higher in several types of cancer cells, even though the levels of ACAT1 protein are about the same. The reason is that the protein clusters together as tetramers in cancer cells. Tyrosine kinases, often on overdrive in cancer cells, “hijack” ACAT1 and nudge it into tetramers, which are enzymatically more active.

But arecoline, identified in a screen of 2000 FDA-approved small molecule compounds, can inhibit ACAT1 and prevent it from forming tetramers. Arecoline forms a chemical bond with part of the ACAT1 protein, the researchers showed.

Arecoline appears to do what the researchers proposed it would: it steers cells’ metabolism away from glycolysis. The compound inhibited the growth of human lung cancer and leukemia cells both in culture and grafted into mice, and did not affect the growth of normal blood cells.

The enzyme ACAT1 seems to have a double role. It breaks down ketones and the amino acid isoleucine, and it also modifies other proteins through acetylation, which is how it regulates the Warburg effect.

Genetic mutations in ACAT1 lie behind a very rare metabolic disorder called beta-ketothiolase deficiency. Complete inhibition of ACAT1 could induce side effects resembling that disorder. But when the Winship team incompletely “knocked down” ACAT1 in cells using arecoline or genetic tools, the main effect was on protein acetylation, not on ketone metabolism, Chen says.

While the researchers did not see obvious toxicity when treating mice with arecoline, more extensive pharmacokinetic and toxicology studies with arecoline and similar compounds are needed, he says.

Citation: “Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth”
Jun Fan, Ruiting Lin, Siyuan Xia, Dong Chen, Shannon E. Elf, Shuangping Liu, Yaozhu Pan, Haidong Xu, Zhiyu Qian, Mei Wang, Changliang Shan, Lu Zhou, Qun-Ying Lei, Yuancheng Li, Hui Mao, Benjamin H. Lee, Jessica Sudderth, Ralph J. DeBerardinis, Guojing Zhang, Taofeek Owonikoko, Manila Gaddh, Martha L. Arellano, Hanna J. Khoury, Fadlo R. Khuri, Sumin Kang, Paul W. Doetsch, Sagar Lonial, Titus J. Boggon, Walter J. Curran1, Jing Chen.
Molecular Cell 2016
DOI: http://dx.doi.org/10.1016/j.molcel.2016.10.014
Research funding: National Cancer Institute, T.J. Martell Foundation,  American Cancer Society seed grant and Georgia Cancer Coalition.
Adapted from press release by Emory Health Sciences.

Therapeutic Antibody conjugates proven clinically effective with acceptable toxicity

Antibody Drug Conjugates (ADCs) have shown a clearly documented efficacy and acceptable toxicity and can be easily implemented in oncology departments where chemotherapy administration is a routine practice. A similar efficacy with acceptable toxicity has been documented with Antibody Radionuclide Conjugates (ARCs) which need to be injected with the help of a nuclear medicine department which can be a limitation for referral from an oncologist.

In a review collecting the clinical results of 11 studies including 598 patients treated with 6 Antibody Drug Conjugates and 9 studies (including 377 patients treated with 5 Antibody Radionuclide Conjugates), toxicity was generally less frequent with Antibody Drug Conjugates than with Antibody Radionuclide Conjugates but often led to more uncomfortable side effects. Both conjugates have shown some clinical efficacy in terms of survival (progression free survival or overall survival) depending on the tumor type, radiosensitive or not.

The good results of both conjugates could be significantly improved in the future. Targeting Cancer Stem Cells (CSC) using both cytotoxic payloads (drugs or radionuclides) could delay tumor relapse. Preclinical studies have shown a promising therapeutic index with long-term tumor regression warranting a clinical application.

Efficacy of Antibody Radionuclide Conjugates could be improved with the use of alpha-emitting radionuclides which deliver a high fraction of their energy inside the targeted tumor cell leading to highly efficient killing especially for isolated tumor cells or clusters of malignant cells in the body.

The efficacy of both Antibody Drug Conjugates and Antibody Radionuclide Conjugates could be enhanced by parallel treatment with immune checkpoint inhibitors thus providing synergistic immunogenic cell death.

In conclusion therapeutic immunoconjugates using chemotherapeutic drug or radionuclides as cytotoxic payloads have clearly shown clinical efficacy, which could be significantly improved in the near future.

Citation: Chatal, Jean-François, Françoise Kraeber-Bodéré, Caroline Bodet-Milin, and Caroline Rousseau. “Therapeutic Immunoconjugates. Which Cytotoxic Payload: Chemotherapeutic Drug (ADC) or Radionuclide (ARC)?.” Current Cancer Therapy Reviews 12, no. 1 (2016): 54-65.
DOI: http://dx.doi.org/10.2174/1573394712666160805121312
Adapted from press release by Bentham Science Publishers.