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Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development

Reporter: Amandeep Kaur, B.Sc., M.Sc.

In early February, Prof. Eran Segal updated in one of his tweets and mentioned that “We say with caution, the magic has started.”

The article reported that this statement by Prof. Segal was due to decreasing cases of COVID-19, severe infection cases and hospitalization of patients by rapid vaccination process throughout Israel. Prof. Segal emphasizes in another tweet to remain cautious over the country and informed that there is a long way to cover and searching for scientific solutions.

A daylong webinar entitled “COVID-19: The epidemic that rattles the world” was a great initiative by Weizmann Institute to share their scientific knowledge about the infection among the Israeli institutions and scientists. Prof. Gideon Schreiber and Dr. Ron Diskin organized the event with the support of the Weizmann Coronavirus Response Fund and Israel Society for Biochemistry and Molecular Biology. The speakers were invited from the Hebrew University of Jerusalem, Tel-Aviv University, the Israel Institute for Biological Research (IIBR), and Kaplan Medical Center who addressed the molecular structure and infection biology of the virus, treatments and medications for COVID-19, and the positive and negative effect of the pandemic.

The article reported that with the emergence of pandemic, the scientists at Weizmann started more than 60 projects to explore the virus from different range of perspectives. With the help of funds raised by communities worldwide for the Weizmann Coronavirus Response Fund supported scientists and investigators to elucidate the chemistry, physics and biology behind SARS-CoV-2 infection.

Prof. Avi Levy, the coordinator of the Weizmann Institute’s coronavirus research efforts, mentioned “The vaccines are here, and they will drastically reduce infection rates. But the coronavirus can mutate, and there are many similar infectious diseases out there to be dealt with. All of this research is critical to understanding all sorts of viruses and to preempting any future pandemics.”

The following are few important projects with recent updates reported in the article.

Mapping a hijacker’s methods

Dr. Noam Stern-Ginossar studied the virus invading strategies into the healthy cells and hijack the cell’s systems to divide and reproduce. The article reported that viruses take over the genetic translation system and mainly the ribosomes to produce viral proteins. Dr. Noam used a novel approach known as ‘ribosome profiling’ as her research objective and create a map to locate the translational events taking place inside the viral genome, which further maps the full repertoire of viral proteins produced inside the host.

She and her team members grouped together with the Weizmann’s de Botton Institute and researchers at IIBR for Protein Profiling and understanding the hijacking instructions of coronavirus and developing tools for treatment and therapies. Scientists generated a high-resolution map of the coding regions in the SARS-CoV-2 genome using ribosome-profiling techniques, which allowed researchers to quantify the expression of vital zones along the virus genome that regulates the translation of viral proteins. The study published in Nature in January, explains the hijacking process and reported that virus produces more instruction in the form of viral mRNA than the host and thus dominates the translation process of the host cell. Researchers also clarified that it is the misconception that virus forced the host cell to translate its viral mRNA more efficiently than the host’s own translation, rather high level of viral translation instructions causes hijacking. This study provides valuable insights for the development of effective vaccines and drugs against the COVID-19 infection.

Like chutzpah, some things don’t translate

Prof. Igor Ulitsky and his team worked on untranslated region of viral genome. The article reported that “Not all the parts of viral transcript is translated into protein- rather play some important role in protein production and infection which is unknown.” This region may affect the molecular environment of the translated zones. The Ulitsky group researched to characterize that how the genetic sequence of regions that do not translate into proteins directly or indirectly affect the stability and efficiency of the translating sequences.

Initially, scientists created the library of about 6,000 regions of untranslated sequences to further study their functions. In collaboration with Dr. Noam Stern-Ginossar’s lab, the researchers of Ulitsky’s team worked on Nsp1 protein and focused on the mechanism that how such regions affect the Nsp1 protein production which in turn enhances the virulence. The researchers generated a new alternative and more authentic protocol after solving some technical difficulties which included infecting cells with variants from initial library. Within few months, the researchers are expecting to obtain a more detailed map of how the stability of Nsp1 protein production is getting affected by specific sequences of the untranslated regions.

The landscape of elimination

The article reported that the body’s immune system consists of two main factors- HLA (Human Leukocyte antigen) molecules and T cells for identifying and fighting infections. HLA molecules are protein molecules present on the cell surface and bring fragments of peptide to the surface from inside the infected cell. These peptide fragments are recognized and destroyed by the T cells of the immune system. Samuels’ group tried to find out the answer to the question that how does the body’s surveillance system recognizes the appropriate peptide derived from virus and destroy it. They isolated and analyzed the ‘HLA peptidome’- the complete set of peptides bound to the HLA proteins from inside the SARS-CoV-2 infected cells.

After the analysis of infected cells, they found 26 class-I and 36 class-II HLA peptides, which are present in 99% of the population around the world. Two peptides from HLA class-I were commonly present on the cell surface and two other peptides were derived from coronavirus rare proteins- which mean that these specific coronavirus peptides were marked for easy detection. Among the identified peptides, two peptides were novel discoveries and seven others were shown to induce an immune response earlier. These results from the study will help to develop new vaccines against new coronavirus mutation variants.

Gearing up ‘chain terminators’ to battle the coronavirus

Prof. Rotem Sorek and his lab discovered a family of enzymes within bacteria that produce novel antiviral molecules. These small molecules manufactured by bacteria act as ‘chain terminators’ to fight against the virus invading the bacteria. The study published in Nature in January which reported that these molecules cause a chemical reaction that halts the virus’s replication ability. These new molecules are modified derivates of nucleotide which integrates at the molecular level in the virus and obstruct the works.

Prof. Sorek and his group hypothesize that these new particles could serve as a potential antiviral drug based on the mechanism of chain termination utilized in antiviral drugs used recently in the clinical treatments. Yeda Research and Development has certified these small novel molecules to a company for testing its antiviral mechanism against SARS-CoV-2 infection. Such novel discoveries provide evidences that bacterial immune system is a potential repository of many natural antiviral particles.

Resolving borderline diagnoses

Currently, Real-time Polymerase chain reaction (RT-PCR) is the only choice and extensively used for diagnosis of COVID-19 patients around the globe. Beside its benefits, there are problems associated with RT-PCR, false negative and false positive results and its limitation in detecting new mutations in the virus and emerging variants in the population worldwide. Prof. Eran Elinavs’ lab and Prof. Ido Amits’ lab are working collaboratively to develop a massively parallel, next-generation sequencing technique that tests more effectively and precisely as compared to RT-PCR. This technique can characterize the emerging mutations in SARS-CoV-2, co-occurring viral, bacterial and fungal infections and response patterns in human.

The scientists identified viral variants and distinctive host signatures that help to differentiate infected individuals from non-infected individuals and patients with mild symptoms and severe symptoms.

In Hadassah-Hebrew University Medical Center, Profs. Elinav and Amit are performing trails of the pipeline to test the accuracy in borderline cases, where RT-PCR shows ambiguous or incorrect results. For proper diagnosis and patient stratification, researchers calibrated their severity-prediction matrix. Collectively, scientists are putting efforts to develop a reliable system that resolves borderline cases of RT-PCR and identify new virus variants with known and new mutations, and uses data from human host to classify patients who are needed of close observation and extensive treatment from those who have mild complications and can be managed conservatively.

Moon shot consortium refining drug options

The ‘Moon shot’ consortium was launched almost a year ago with an initiative to develop a novel antiviral drug against SARS-CoV-2 and was led by Dr. Nir London of the Department of Chemical and Structural Biology at Weizmann, Prof. Frank von Delft of Oxford University and the UK’s Diamond Light Source synchroton facility.

To advance the series of novel molecules from conception to evidence of antiviral activity, the scientists have gathered support, guidance, expertise and resources from researchers around the world within a year. The article reported that researchers have built an alternative template for drug-discovery, full transparency process, which avoids the hindrance of intellectual property and red tape.

The new molecules discovered by scientists inhibit a protease, a SARS-CoV-2 protein playing important role in virus replication. The team collaborated with the Israel Institute of Biological Research and other several labs across the globe to demonstrate the efficacy of molecules not only in-vitro as well as in analysis against live virus.

Further research is performed including assaying of safety and efficacy of these potential drugs in living models. The first trial on mice has been started in March. Beside this, additional drugs are optimized and nominated for preclinical testing as candidate drug.

Source: https://www.weizmann.ac.il/WeizmannCompass/sections/features/the-vaccines-are-here-and-research-abounds

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Identification of Novel genes in human that fight COVID-19 infection

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

https://pharmaceuticalintelligence.com/2021/04/19/identification-of-novel-genes-in-human-that-fight-covid-19-infection/

Fighting Chaos with Care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

https://pharmaceuticalintelligence.com/2021/04/13/fighting-chaos-with-care/

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD

https://pharmaceuticalintelligence.com/2020/12/28/mechanistic-link-between-sars-cov-2-infection-and-increased-risk-of-stroke-using-3d-printed-models-and-human-endothelial-cells/

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Tiny biologic drug to fight COVID-19 show promise in animal models

Reporter : Irina Robu, PhD

A research team at University of Pittsburg School of Medicine identified an antibody component that is 10 times smaller than a full-sized antibody. Their research published in Cell, indicates that the drug, Ab8 based on it is effective in mice and hamsters. The research was started by screening a library of about 100 billion antibody fragments to identify candidates that bound tightly to the spike protein on SARS-CoV-2’s surface, which the virus uses to enter and infect human cells.

A typical antibody consists of two heavy chains and two light chains. The chosen molecule is the variable domain of the heavy chain of an immunoglobulin, which is a type of antibody. The heavy chain variable domain is essential for binding with an antigen. Ab8 was created by fusing the variable, heavy chain domain with part of the immunoglobulin tail region, giving it immune functions but doing so with a molecule that’s about half the size of a full immunoglobulin.

The smaller size of the antibody can improve the therapeutic efficacy for infectious diseases and can be delivered through inhalation. Their research showed that Ab8 completely neutralized SARS-CoV-2 in lab dishes. The drug developed showed that inhibited the virus in lung tissue in animal body even at the lowest dose 2 mg/kg as compared to untreated controls.

The research team is looking to determine the drug effect in hamsters, which were reported to have better clinical signatures of COVID-19. And the hamsters that got the drug display less severe pneumonia that did the control animals. Drugs with alternative administration routers could provide additions to the first wave of COVID-19 therapies and vaccines.

What is more important, Ab8 does not appear to bind to human cells which is a good sign that it won’t have negative side effects.

SOURCE

https://www.fiercebiotech.com/research/small-sized-biologic-against-covid-19-shows-promise-animal-models

 

 

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“Repurposing” Off-patent Drugs offers big hopes of New Treatments

Reporter: Irina Robu, PhD

Given the substantial costs and the slow pace of drug discovery and development, repurposing old drugs has become a practice, partly because it involves the use of already developed compounds. Yet, there is lack of clinical interest in repurposing off patent drugs.

However, the scale of the opportunity for drug repurposing is huge. Initially approved for one disease, these drugs went off-patent and now show potential in other diseases. Even so, many non-profit groups see promise in supporting trials into drug repurposing. There is a huge untapped medicine chest of generic drugs with unexploited uses. These generic drugs are often cheap, already approved, off-patent and relatively quick to develop, whereas new drugs can cost millions of dollars to develop, test and 45% of the drugs fail in clinical trials.

However, numerous non-profit groups see potential in supporting trials into drug repurposing. Epidemiological data can offer enticing leads. Yet, clinical trials for these drugs are costly, but the benefits can be huge. The Drugs for Neglected Diseases Initiative, a Swiss non-profit research group, supported research into fexinidazole, which was abandoned by a pharma at an early stage. The drug showed to have antiparasitic qualities. However, after years of work in January 2020, it was approved for sleeping sickness in the Democratic Republic of Congo. It is the first oral medicine for the disease, and works for all stages of it.

Up till now, when it comes to cancer the most promising generic pills are known. Cancer Research, a UK based charity is testing aspirin to see if can stop cancer from recurring; metformin in a large prostate-cancer trial; and an anti-fungal medication to treat bowel cancer. At the same time, the Anticancer Fund in Brussels hopes that propranolol in treating cancers of the inner lining of blood vessels and pancreatic cancer. Propranolol is a generic 1960s beta-blocker used for a wide range of ailments such as hypertension, anxiety and migraine. If approved for cancer, its cost would be negligible in comparison the tens of thousands of dollars a month usually charged for cancer medicines.

Money seems the crucial constraint with these drugs, in addition to the clinical trials needed to have these drugs updated and relabeled. Only the makers or original developers of a drug are permitted to adjust its label. Sanofi, based in Paris, was the firm that requested regulatory review of fexinidazole for sleeping sickness, while the research was a charitable effort. But drug firms are not forced to support non-commercial efforts to repurpose drugs. And outside the industry it is tough to find the legal expertise to be able to do the  necessary paperwork.

As non-profits make progress in repurposing, corporate interest may be rising. In terms of achieving new treatment options, this is good news. But it will not bring cheaper medicines in areas traditionally neglected by the drug industry. Firms will focus on finding ways to patent the new uses and charge high prices for the finished product.

If governments need cheaper drugs, non-profits will need financial incentives and a cooperative regulatory framework. They include making regulators give free advice and waive approval fees, and a public fund to support repurposing. Yet, when drugs are approved, investors are paid back by the public health service, which makes savings by using the newly approved generic drugs.

SOURCE

https://www.economist.com/international/2019/02/28/repurposing-off-patent-drugs-offers-big-hopes-of-new-treatments?fsrc=scn/tw/te/bl/ed/crosspurposesrepurposingoffpatentdrugsoffersbighopesofnewtreatmentsinternational

 

Other related articles published in this Online Scientific Open Access Journal include:

 

The Castleman Disease Research Network publishes Phase 1 Results of Drug Repurposing Database for COVID-19

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/06/27/the-castleman-disease-research-network-publishes-phase-1-results-of-drug-repurposing-database-for-covid-19/

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

Reporter: Stephen J. Williams, PhD

Updated on 07/08/2021  

https://cancerdiscovery.aacrjournals.org/content/early/2021/07/01/2159-8290.CD-20-1741

Session VMS.ET04.01 – Novel Targets and Therapies

Targeting chromatin remodeling-associated genetic vulnerabilities in cancer: PBRM1 defects are synthetic lethal with PARP and ATR inhibitors

Presenter/AuthorsRoman Merial Chabanon, Daphné Morel, Léo Colmet-Daage, Thomas Eychenne, Nicolas Dorvault, Ilirjana Bajrami, Marlène Garrido, Suzanna Hopkins, Cornelia Meisenberg, Andrew Lamb, Theo Roumeliotis, Samuel Jouny, Clémence Astier, Asha Konde, Geneviève Almouzni, Jyoti Choudhary, Jean-Charles Soria, Jessica Downs, Christopher J. Lord, Sophie Postel-Vinay. Gustave Roussy, Villejuif, France, The Francis Crick Institute, London, United Kingdom, Institute of Cancer Research, London, United Kingdom, Sage Bionetworks, Seattle, WA, Institute of Cancer Research, London, United Kingdom, Institute of Cancer Research, London, United Kingdom, Institut Curie, Paris, France, Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France, Gustave Roussy Cancer Campus and U981 INSERM, ATIP-Avenir group, Villejuif, FranceDisclosures R.M. Chabanon: None. D. Morel: None. L. Colmet-Daage: None. T. Eychenne: None. N. Dorvault: None. I. Bajrami: None. M. Garrido: None. S. Hopkins: ; Fishawack Group of Companies. C. Meisenberg: None. A. Lamb: None. T. Roumeliotis: None. S. Jouny: None. C. Astier: None. A. Konde: None. G. Almouzni: None. J. Choudhary: None. J. Soria: ; Medimmune/AstraZeneca. ; Astex. ; Gritstone. ; Clovis. ; GSK. ; GamaMabs. ; Lilly. ; MSD. ; Mission Therapeutics. ; Merus. ; Pfizer. ; PharmaMar. ; Pierre Fabre. ; Roche/Genentech. ; Sanofi. ; Servier. ; Symphogen. ; Takeda. J. Downs: None. C.J. Lord: ; AstraZeneca. ; Merck KGaA. ; Artios. ; Tango. ; Sun Pharma. ; GLG. ; Vertex. ; Ono Pharma. ; Third Rock Ventures. S. Postel-Vinay: ; Merck KGaA. ; Principal investigator of clinical trials for Gustave Roussy.; Boehringer Ingelheim. ; Principal investigator of clinical trials for Gustave Roussy.; Roche. ; Principal investigator of clinical trials for Gustave Roussy. Benefited from reimbursement for attending symposia.; AstraZeneca. ; Principal investigator of clinical trials for Gustave Roussy.; Clovis. ; Principal investigator of clinical trials for Gustave Roussy.; Bristol-Myers Squibb. ; Principal investigator of clinical trials for Gustave Roussy.; Agios. ; Principal investigator of clinical trials for Gustave Roussy.; GSK.AbstractAim: Polybromo-1 (PBRM1), a specific subunit of the pBAF chromatin remodeling complex, is frequently inactivated in cancer. For example, 40% of clear cell Renal Cell Carcinoma (ccRCC) and 15% of cholangiocarcinoma present deleterious PBRM1 mutations. There is currently no precision medicine-based therapeutic approach that targets PBRM1 defects. To identify novel, targeted therapeutic strategies for PBRM1-defective cancers, we carried out high-throughput functional genomics and drug screenings followed by in vitro and in vivo validation studies.
Methods: High-throughput siRNA-drug sensitization and drug sensitivity screens evaluating > 150 cancer-relevant small molecules in dose-response were performed in Pbrm1 siRNA-transfected mouse embryonic stem cells (mES) and isogenic PBRM1-KO or -WT HAP1 cells, respectively. After identification of PBRM1-selective small molecules, revalidation was carried out in a series of in-house-generated isogenic models of PBRM1 deficiency – including 786-O (ccRCC), A498 (ccRCC), U2OS (osteosarcoma) and H1299 (non-small cell lung cancer) human cancer cell lines – and non-isogenic ccRCC models, using multiple clinical compounds. Mechanistic dissection was performed using immunofluorescence, RT-qPCR, western blotting, DNA fiber assay, transcriptomics, proteomics and DRIP-sequencing to evaluate markers of DNA damage response (DDR), replication stress and cell-autonomous innate immune signaling. Preclinical data were integrated with TCGA tumor data.
Results: Parallel high-throughput drug screens independently identified PARP inhibitors (PARPi) as being synthetic lethal with PBRM1 defects – a cell type-independent effect which was exacerbated by ATR inhibitors (ATRi) and which we revalidated in vitro in isogenic and non-isogenic systems and in vivo in a xenograft model. PBRM1 defects were associated with increased replication fork stress (higher γH2AX and RPA foci levels, decreased replication fork speed and increased ATM checkpoint activation), R-loop accumulation and enhanced genomic instability in vitro; these effects were exacerbated upon PARPi exposure. In patient tumor samples, we also found that PBRM1-mutant cancers possessed a higher mutational load. Finally, we found that ATRi selectively activated the cGAS/STING cytosolic DNA sensing pathway in PBRM1-deficient cells, resulting in increased expression of type I interferon genes.
Conclusion: PBRM1-defective cancer cells present increased replication fork stress, R-loop formation, genome instability and are selectively sensitive to PARPi and ATRi through a synthetic lethal mechanism that is cell type-independent. Our data provide the pre-clinical rationale for assessing PARPi as a monotherapy or in combination with ATRi or immune-modulating agents in molecularly-selected patients with PBRM1-defective cancers.

1057 – Targeting MTHFD2 using first-in-class inhibitors kills haematological and solid cancer through thymineless-induced replication stress

Presenter/AuthorsThomas Helleday. University of Sheffield, Sheffield, United KingdomDisclosures T. Helleday: None.AbstractSummary
Thymidine synthesis pathways are upregulated pathways in cancer. Since the 1940s, targeting nucleotide and folate metabolism to induce thymineless death has remained first-line anti-cancer treatment. Recent discoveries that showing cancer cells have rewired networks and exploit unique enzymes for proliferation, have renewed interest in metabolic pathways. The cancer-specific expression of MTHFD2 has gained wide-spread attention and here we describe an emerging role for MTHFD2 in the DNA damage response (DDR). The folate metabolism enzyme MTHFD2 is one of the most consistently overexpressed metabolic enzymes in cancer and an emerging anticancer target. We show a novel role for MTHFD2 being essential for DNA replication and genomic stability in cancer cells. We describe first-in-class nanomolar MTHFD2 inhibitors (MTHFD2i), with protein co-crystal structures demonstrating binding in the active site of MTHFD2 and engaging with the target in cells and tumours. We show MTHFD2i reduce replication fork speed and induce replication stress, followed by S phase arrest, apoptosis and killing of a range of haematological and solid cancer cells in vitro and in vivo, with a therapeutic window spanning up to four orders of magnitude compared to non-transformed cells. Mechanistically, MTHFD2i prevent thymidine production leading to mis-incorporation of uracil into DNA and replication stress. As MTHFD2 expression is cancer specific there is a potential of MTHFD2i to synergize with other treatments. Here, we show MTHFD2i synergize with dUTPase inhibitors as well as other DDR inhibitors and demonstrate the mechanism of action. These results demonstrate a new link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically.
Keywords
MTHFD2, one-carbon metabolism, folate metabolism, DNA replication, replication stress, synthetic lethal, thymineless death, small-molecule inhibitor, DNA damage response

1060 – Genetic and pharmacologic inhibition of Skp2, an E3 ubiquitin ligase and RB1-target, has antitumor activity in RB1-deficient human and mouse small cell lung cancer (SCLC)

Presenter/Authors
Hongling ZhaoVineeth SukrithanNiloy IqbalCari NicholasYingjiao XueJoseph LockerJuntao ZouLiang ZhuEdward L. Schwartz. Albert Einstein College of Medicine, Bronx, NY, Albert Einstein College of Medicine, Bronx, NY, Albert Einstein College of Medicine, Bronx, NY, University of Pittsburgh Medical Center, Pittsburgh, PA, Albert Einstein College of Medicine, Bronx, NY
Disclosures
 H. Zhao: None. V. Sukrithan: None. N. Iqbal: None. C. Nicholas: None. Y. Xue: None. J. Locker: None. J. Zou: None. L. Zhu: None. E.L. Schwartz: None.
Abstract
The identification of driver mutations and their corresponding targeted drugs has led to significant improvements in the treatment of non-small cell lung cancer (NSCLC) and other solid tumors; however, similar advances have not been made in the treatment of small cell lung cancer (SCLC). Due to their aggressive growth, frequent metastases, and resistance to chemotherapy, the five-year overall survival of SCLC is less than 5%. While SCLC tumors can be sensitive to first-line therapy of cisplatin and etoposide, most patients relapse, often in less than 3 months after initial therapy. Dozens of drugs have been tested clinically in SCLC, including more than 40 agents that have failed in phase III trials.
The near uniform bi-allelic inactivation of the tumor suppressor gene RB1 is a defining feature of SCLC. RB1 is mutated in highly aggressive tumors, including SCLC, where its functional loss, along with that of TP53, is both required and sufficient for tumorigenesis. While it is known that RB1 mutant cells fail to arrest at G1/S in response to checkpoint signals, this information has not led to effective strategies to treat RB1-deficient tumors, and it has been challenging to develop targeted drugs for tumors that are driven by the loss of gene function.
Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/p53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, and we confirmed this was the mechanism of protection in the RP-Skp2 KO mice by using the knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind to and/or inhibit Skp2 induced apoptosis and inhibited SCLC cell growth. In a panel of SCLC cell lines, growth inhibition by a Skp2 inhibitor was not correlated with sensitivity/resistance to etoposide. Targeting Skp2 also had in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using the genetic and pharmacologic approaches, antitumor activity was seen in vivo in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. The identification and validation of an actionable target downstream of RB1 could have a broad impact on treatment of SCLC and other advanced tumors with mutant RB1, for which there are currently no targeted therapies available.

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3D-Printed Brain Clear the Way to Find Cancer Treatments

Reported by: Irina Robu, PhD

Glioblastomas are aggressive and malignant grade IV brain tumors and can located wherever in the brain and do not regularly spread outside of the brain. Common symptoms patients with glioblastoma experience include headaches, seizures, confusion, memory loss, muscle weakness, visual changes, language deficit, and cognitive changes. Glioblastomas tend to affect older individuals (age 45 to 70) with rare occurrences in children. Treatment methods typically include a combination of surgery, chemotherapy, radiation therapy, and alternating electric fields therapy.

Scientists at Northwestern University developed a technique to study their fast spreading cancer using a 3D structure made of agglomeration of human brain cells and biomaterials, which can help doctors better understand how the tumor grows and speed up the potential discovery of novel drugs to fight it. A water-based substance serves as a matrix to hold the cells into place. However, inside the living brain, scientists can’t observe how the tumor cells grow or respond the treatment and they have to use mice/rats to understand tumor development. Animal studies are expensive and time consuming, but the 3D printed live tissue allows researchers to study glioblastoma to be studied more directly.

To understand what happens inside the 3D model, the researchers used a laser to scan the sample and create a snapshot of the cellular structure. This combination allows them to assess the effectiveness of a commonly used chemotherapy drug, temozolomide. The drug, temozolomide kills glioblastoma cells in two-dimensional models, but when put into a three-dimensional one, the tumor rebounded which implies that the drug did not work in the long term.

This 3D model may be able to speed up that process to weed out ineffective drugs first, confirming that only the most promising ones move to animal, and eventually human, trials.

SOURCE

A 3D-printed brain could make it easier to find cancer treatments

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37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 10, 2019: Deals and Announcements

Reporter: Stephen J. Williams, Ph.D.

From Biospace.com

 

JP Morgan Healthcare Conference Update: Sage, Mersana, Shutdown Woes and Babies

Speaker presenting to audience at a conference

With the J.P. Morgan Healthcare Conference winding down, companies remain busy striking deals and informing investors about pipeline advances. BioSpace snagged some of the interesting news bits to come out of the conference from Wednesday.

SAGE Therapeutics – Following a positive Phase III report that its postpartum depression treatment candidate SAGE-217 hit the mark in its late-stage clinical trial, Sage Therapeutics is eying the potential to have multiple treatment options available for patients. At the start of J.P. Morgan, Sage said that patients treated with SAGE-217 had a statistically significant improvement of 17.8 points in the Hamilton Rating Scale for Depression, compared to 13.6 for placebo. The company plans to seek approval for SAGE-2017, but before that, the FDA is expected to make a decision on Zulresso in March. Zulresso already passed muster from advisory committees in November, and if approved, would be the first drug specifically for postpartum depression. In an interview with the Business Journal, Chief Business Officer Mike Cloonan said the company believes there is room in the market for both medications, particularly since the medications address different patient populations.

 

Mersana Therapeutics – After a breakup with Takeda Pharmaceutical and the shelving of its lead product, Cambridge, Mass.-based Mersana is making a new path. Even though a partial clinical hold was lifted following the death of a patient the company opted to shelve development of XMT-1522. During a presentation at JPM, CEO Anna Protopapas noted that many other companies are developing therapies that target the HER2 protein, which led to the decision, according to the Boston Business Journal. Protopapas said the HER2 space is highly competitive and now the company will focus on its other asset, XMT-1536, an ADC targeting NaPi2b, an antigen highly expressed in the majority of non-squamous NSCLC and epithelial ovarian cancer. XMT-1536 is currently in Phase 1 clinical trials for NaPi2b-expressing cancers, including ovarian cancer, non-small cell lung cancer and other cancers. Data on XMT-1536 is expected in the first half of 2019.

Novavax – During a JPM presentation, Stan Erck, CEO of Novavax, pointed to the company’s RSV vaccine, which is in late-stage development. The vaccine is being developed for the mother, in order to protect an infant. The mother transfers the antibodies to the infant, which will provide the baby with protection from RSV in its first six months. Erck called the program historic. He said the Phase III program is in its fourth year and the company has vaccinated 4,636 women. He said they are tracking the women and the babies. Researchers call the mothers every week through the first six months of the baby’s life to acquire data. Erck said the company anticipates announcing trial data this quarter. If approved, Erck said the market for the vaccine could be a significant revenue driver.

“You have 3.9 million birth cohorts and we expect 80 percent to 90 percent of those mothers to be vaccinated as a pediatric vaccine and in the U.S. the market rate is somewhere between $750 million and a $1 billion and then double that for worldwide market. So it’s a large market and we will be first to market in this,” Erck said, according to a transcript of the presentation.

Denali Therapeutics – Denali forged a collaboration with Germany-based SIRION Biotech to develop gene therapies for central nervous disorders. The two companies plan to develop adeno-associated virus (AAV) vectors to enable therapeutics to cross the blood-brain barrier for clinical applications in neurodegenerative diseases including Parkinson’s, Alzheimer’s disease, ALS and certain other diseases of the CNS.

AstraZeneca – Pharma giant AstraZeneca reported that in 2019 net prices on average across the portfolio will decrease versus 2018. With a backdrop of intense public and government scrutiny over pricing, Market Access head Rick Suarez said the company is increasing its pricing transparency. Additionally, he said the company is looking at new ways to price drugs, such as value-based reimbursement agreements with payers, Pink Sheet reported.

Amarin Corporation – As the company eyes a potential label expansion approval for its cardiovascular disease treatment Vascepa, Amarin Corporation has been proactively hiring hundreds of sales reps. In the fourth quarter, the company hired 265 new sales reps, giving the company a sales team of more than 400, CEO John Thero said. Thero noted that is a label expansion is granted by the FDA, “revenues will increase at least 50 percent over what we did in the prior year, which would give us revenues of approximate $350 million in 2019.”

Government Woes – As the partial government shutdown in the United States continues into its third week, biotech leaders at JPM raised concern as the FDA’s carryover funds are dwindling. With no new funding coming in, reviews of New Drug Applications won’t be able to continue past February, Pink Sheet said. While reviews are currently ongoing, no New Drug Applications are being accepted by the FDA at this time. With the halt of NDA applications, that has also caused some companies to delay plans for an initial public offering. It’s hard to raise potential investor excitement without the regulatory support of a potential drug approval. During a panel discussion, Jonathan Leff, a partner at Deerfield Management, noted that the ongoing government shutdown is a reminder of how “overwhelmingly dependent the whole industry of biotech and drug development is on government,” Pink Sheet said.

Other posts on the JP Morgan 2019 Healthcare Conference on this Open Access Journal include:

#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology

36th Annual J.P. Morgan HEALTHCARE CONFERENCE January 8 – 11, 2018

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: #JPM2019 for Jan. 8, 2019; Opening Videos, Novartis expands Cell Therapies, January 7 – 10, 2019, Westin St. Francis Hotel | San Francisco, California

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 8, 2019: Deals and Announcements

 

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Recents Thoughts of Biotech Innovation: 2015 2016

From WorldofDTCMarketing

Can’t innovate ? Buy small biotech companies that can

cloud-innovationOn a week where a lot of people are taking their final summer vacations the news is that Amgen is buying Onyx and AstraZeneca Plc took a further step to bolster its pipeline of new cancer drugs on Monday by agreeing to acquire privately held U.S. biotech company Amplimmune for up to $500 million.  On paper it’s a good business move but as big pharma companies gobble up small biotech companies they bring with then antiquated processes and business people who are thinking about the bottom line rather than patients.  The results ?  Innovation that led these smaller biotech companies to develop new drugs will be stymied by a bureaucratic business model.

There is a reason why, after being acquired, that so many employees of smaller biotech companies leave.  Either they don’t want to work for big a big pharma bureaucracy or the acquiring company determines that these people are not needed and shows them the door.  Behind all this are people who provided the start-up funding and want to cash in without awaiting the lengthy process of developing new drugs.  In the end however it’s patients who loose.

bureaucracy

Last week Steve Ballmer, the CEO of Microsoft, announced his resignation.  There is a correlation between what happened at Microsoft and the challenges for big pharma.  Steve was forced out because Microsoft became a huge bureaucracy and could not innovate fast enough.  Those of us who have worked in pharma know of the endless 9-5 meetings to move even small projects forward.  Amgen’s culture revolves around back-to-back meetings with executives from other big pharma companies who are trying to put their power on display.  It’s only a matter of time before people from Onyx leave because of Amgen’s prohibitive culture.

Unknown

Until the costs of developing and launching new drugs is lower more and more innovative biotech firms are going to have a for sale sign hanging in the window hoping big pharma can help investors cash in.

And in a Commentary on CNBC

This is biotech’s real problem

Robert J. Mulroy, president and CEO of Merrimack

Thursday, 1 Oct 2015 | 9:38 AM ET

1

COMMENTJoin the Discussion

Here’s a challenge — name a biotech that’s not a small company with one potential blockbuster in the works or an industry giant that’s acquiring the hottest new technologies. Got one? Great! Now try to name four more.

Biotech

Jian Wan | Vetta | Getty Images

The fact is, midsize biotechs (Ironwood Pharmaceuticals andMedivation are couple of examples) are a rarity these days, and that’s a problem for patients, doctors and investors. Start-ups that are in the process of developing and drawing from a foundation of knowledge are often acquired once they have a promising candidate in the pipeline. If the associated research teams aren’t immediately jettisoned (just when their potential for broader breakthroughs is surging), the top innovators go off to launch another venture that doesn’t build on their current research.

There’s also enormous pressure to focus on that “next big thing” that can crowd out other innovations for patients, while blocking valuable, in-depth examination of existing treatments. In oncology, drug combinations (like Genentech’s combination of Herceptin, pertuzumab and docetaxel to treat HER-2 breast cancer) are making huge strides in prolonging patients’ lives. Such combinations require understanding how specific tumors grow, and designing diagnostics that tell doctors whether a patient’s tumor fits that profile. The problem? Not enough small biotechs have the luxury of developing that understanding before they’re acquired so that big biotechs can gain another drug candidate.

As the CEO of a cancer-focused biotech that’s spent the last 15 years building a diverse product pipeline — the lead candidate is under FDA review with a decision expected next month — my view is that pursuing individual drug targets will bring limited success. Cancer is the ultimate engineering challenge, and effective treatments need to address more than a single facet of the problem.

The real winners in the industry will be the companies that understand how their therapies work in combinations with their own and competing therapies, and help physicians make sense of the explosion of new treatments via companion diagnostics. In fact, regulators could potentially require a more integrated approach to manage the ever-increasing influx of new drugs and data. In August, the American Society of Clinical Oncology issued guidelines for doctors on interpreting multi-gene tests for cancer susceptibility, acknowledging the need for more education and regulation.

Most oncology biotech start-ups dream of developing such an integrated approach. But it takes time and money, and an environment that prioritizes in-depth scientific research.

Doing well by patients, doctors and investors means pursuing sustainable innovation, not just one-offs or single-use purchases. Innovation drives value and can build on itself to address complex challenges. And while innovation takes time and entails risk, it mitigates that risk in the long term.

For example, if you have a deep understanding of how your drug works — say, the tumor-growth mechanisms it disrupts — you can determine whether there are signs that the mechanism it targets is present in a particular patient and then enroll only those patients in clinical trials. That allows for smaller, less expensive trials — and a higher chance of success.

An integrated approach across the industry would allow drug developers to identify responders, and then eliminate the non-responders from clinical trials and from the target population post-approval, ensuring patients only receive treatments likely to benefit them and don’t waste their time enrolling in irrelevant trials.

The current cycle of big pharma acquiring start-ups and dismantling the research teams while divesting in their own R&D appears self-perpetuating, but cracks are showing in the high cost — now in the billions — of bringing a single drug to market.

These companies are dealing with outside pressures that stymie progress. Less than 10 percent of experimental oncology drugs ever get approved. A tactical approach to the pipeline makes sense from a risk-aversion perspective. But sustainable growth requires strategy and investments in the fundamental science work that drives innovation.

Commentary by Robert J. Mulroy, president and CEO of Merrimack, a biotech company focused on cancer treatments. Prior to joining Merrimack, Mr. Mulroy worked as a management consultant in the pharmaceutical and health-care industries. He has served as an advisor to multiple start-up companies in the biotechnology industry.

The New Biotechnology Innovation Organization

Jim's CornerAt BIO, new discoveries in research and development are constantly being made by our members. We take pride in the contributions they have made across a diverse range of biotechnology industries, including: healthcare, agricultural, industrial and environmental.

As one of the world’s strongest catalysts for innovation, our role within the biotechnology community requires us to reflect on who we are, what we do and how we can better serve our members in future.

Biotechnology scientists and entrepreneurs are not just industrious – they are revolutionary, imaginative, inspired, creative, ingenious and inventive. It is these traits that produce innovation.

BIO Logo Vertical RGBAs you may already know, starting today, the Biotechnology Industry Organization will become the Biotechnology Innovation Organization. It’s a one-word name change – from industry to innovation – but the implications are substantial.

Today is a time of tremendous innovation. So much so that our current name no longer best describes our members and our role as one of the world’s leading innovators.

BIO’s members are on the cutting-edge of science and we believe our new name will allow us to build upon our relationships, create new ones and provide our members with better educational and research opportunities.

Our members are discovering scientific breakthroughs and bringing new and innovative therapies to the marketplace. With the help of biotechnology, people are living longer and healthier lives. Our industry embodies innovation and made the world a better place for people everywhere.

Our meaningful innovations also provide the tools to help feed more people, develop new sustainable fuels and products to help protect the planet and devise unique clean technologies to make our environment safer.

In the more than 22 years since its founding, BIO has united scientists, policymakers and the public in a partnership to drive our remarkable progress even further.

It’s important to note that we are not becoming a different organization. We are not altering our mission or the value we deliver to our members.

We will, however, continue to blaze the trail to accelerate cures – connecting thought leaders, building a stronger, more advanced economy and creating jobs to raise the world’s standard of living.

In the coming years, BIO’s diverse membership – from promising startups to global companies in a wide array of biotechnology and related fields – will drive health, life expectancy and improve quality of life for millions of people.

The Biotechnology Innovation Organization will be there to support our members in their tireless effort to make the world a better place to live.

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Invivoscribe, Thermo Fisher Ink Cancer Dx Development Deal, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Invivoscribe, Thermo Fisher Ink Cancer Dx Development Deal

Reporter: Stephen J. Williams, PhD

 

NEW YORK (GenomeWeb) – Invivoscribe Technologies announced today that it has formed a strategic partnership with Thermo Fisher Scientific to develop multiple next-generation sequencing-based in vitro cancer diagnostics.

Under the deal, Invivoscribe will develop and commercialize immune-oncology molecular diagnostics that run on Thermo’s Ion PGM Dx system, as well as associated bioinformatics software for applications in liquid biopsies. The tests will be specifically designed for both the diagnosis and minimal residual disease (MRD) monitoring of various hematologic cancers.

Additional terms of the arrangement were not disclosed.

“We are … very excited to provide our optimized NGS tests with comprehensive bioinformatics software so our customers can perform the entire testing and reporting process, including MRD testing, within their laboratories,” Invivoscribe CEO Jeffrey Miller said in a statement.

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Obesity Pharmaceutics

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Battling the Bulge

Weight-loss drugs that target newly characterized obesity-related receptors and pathways could finally offer truly effective fat control.

By Bob Grant | November 1, 2015

http://www.the-scientist.com//?articles.view/articleNo/44322/title/Battling-the-Bulge/

http://www.the-scientist.com/November2015/NovBioBiz2_640px.jpg

Several years ago, antiobesity drug development was not looking so hot. In 2007, Sanofi-Aventis failed to win US Food and Drug Administration (FDA) approval for rimonabant—a pill that successfully helped people shed pounds—because the drug carried risks of depression and suicidal thoughts. Then, in 2008, Merck pulled the plug on its Phase 3 trials of taranabant because it also engendered suicidal thoughts and neurological effects in some participants. And a decade before those late-stage disappointments, a couple of FDA-approved weight-loss drugs were making headlines for carrying dangerous side effects. In 1997, the FDA pulled the obesity medications fenfluramine (of the wildly popular fen-phen drug combination) and dexfenfluramine (Redux) off the market after research turned up evidence of heart valve damage in people taking the drugs.

By 2009, Big Pharma was backing out of the weight-loss market, with Merck and Pfizer abandoning their programs to develop drugs similar to rimonabant and taranabant, which block cannabinoid receptors in the brain. Although the antiobesity drug market was big—according to CDC estimates, about 35 percent of adults in the U.S. are obese—a blockbuster weight-loss pill that didn’t have serious side effects was proving elusive.

But a few firms, including several small biotechs, decided to stick with it. “Some of the prior experience with drugs on the market, like fen-phen and Redux, have likely led large pharma to view the therapeutic space with some conservatism,” says Preston Klassen, executive vice president and head of global development at Orexigen Therapeutics, a small, California-based firm. “And generally, when you have that situation, smaller companies will step into that void when the science makes sense.” And their perseverance is starting to pay off. After a years-long drought in approvals for antiobesity medications, in the past few years the FDA has approved four new drugs specifically for general obesity: Belviq and Qsymia in 2012, and Contrave and Saxenda in late 2014. Three of these four were developed by small companies whose success hinges on one or a few compounds aimed directly at treating general obesity.

The recent burst of antiobesity drug approvals reflects an evolving appreciation for the molecular intricacies of this multifaceted, chronic disease. Today’s antiobesity drugs—including the four recent approvals and several more in development—have traded the blunt cudgel of appetite suppression for more precise targeting of pathways known to play roles in obesity. “With our understanding of the complex biology of obesity and all of the different molecules and receptors involved in the process, we’re much better able to target those molecules and receptors,” says Arya Sharma, chair in obesity research and management at the University of Alberta in Canada. “These are very specific agents that are designed for very specific actions. There is renewed enthusiasm in this field.”

Looking to combos

In the mid-20th century, the FDA approved several weight-loss drugs, starting with the appetite suppressant desoxyephedrine (methamphetamine hydrochloride) in 1947. Like the other appetite-suppressing drugs the FDA later approved through the 1950s and ’60s, desoxyephedrine accomplished short-term weight loss, but the transient benefit did not justify the side effects of long-term use, such as addiction, psychosis, and violent behavior. In 1973, as the nation voiced concern about the overuse of amphetamines, the FDA decreed that all obesity drugs were approved only for short-term use. The most recently approved obesity drugs, on the other hand, all have the FDA’s okay for long-term weight management.

Three of the newly approved drugs, Contrave, Belviq, and Qsymia, also aim to suppress appetite, and like many previous weight-loss therapies, all do so by targeting the hypothalamus, the brain region thought to be the seat of appetite control. Although the precise mechanism of Belviq, which is manufactured by San Diego–based Arena Pharmaceuticals, is unknown, researchers think that the key is its activation of serotonin-binding 5-HT2C receptors in proopiomelanocortin (POMC) neurons in the hypothalamus. When activated, these neurons reduce appetite and increase energy expenditure, according to Orexigen’s Klassen. His company’s Contrave also activates POMC neurons in the hypothalamus, while at the same time inhibiting opioid receptors, which would otherwise work to shut down POMC neuron firing, in the brain’s mesolimbic reward pathway. Contrave achieves this one-two punch because it is a combination therapy, incorporating two different compounds into a single weight-loss pill.

“The concept of a silver or magic bullet whereby one drug meets all of the needs within the obesity space has thus far proven to be inadequate,” says Klassen. “Right now I think the predominant opinion is that combination therapy is an appropriate way to go.”

Vivus’s Qsymia is also a combination drug, composed of phentermine—the other half of fen-phen and an activator of a G protein–coupled receptor called TAAR1—and an extended-release form of topiramate, an anticonvulsant with weight-loss side effects. Novo Nordisk—one of the few Big Pharma firms that stayed in the obesity game as others fled—is also turning its attention to combo therapies, testing its pipeline of investigational weight-loss compounds with Saxenda, its recently approved medicine that mimics glucagon peptide-1 (GLP-1), an appetite and calorie-intake regulator in the brain. “You need to combine at least two molecules to get the optimum effect,” says Novo Nordisk executive vice president and chief scientific officer Mads Krogsgaard Thomsen. The company has five other weight-loss compounds in development, and “we’re actually combining Saxenda with all of these new molecules,” he adds.

The University of Alberta’s Sharma agrees that combination therapies are a smart approach for attacking the multilayered mechanisms at play in obesity. “You’re dealing with a system that is very complex and very redundant. When you block one, other molecules or other parallel systems kick in,” he says. “My prediction for the future is that in order to get good results, one will have to move toward combinations . . . of more-specific and more-novel agents.”

On the horizon

On the heels of the recent FDA approvals, several new compounds with novel mechanisms of action are making their way through the drug-development pipeline. While most antiobesity drugs to date have aimed to suppress appetite by targeting brain regions involved in feelings of hunger and satiety, Boston-based Zafgen (for which Sharma serves as a paid advisor) is going after methionine aminopeptidase 2 (MetAP2) receptors in the liver and adipose tissue. “We’ve been one of the first ones to show that there is a significant and major weight-regulation center that the body has that exists outside the hypothalamus,” says Zafgen chief medical officer Dennis Kim. “Our drug [beloranib] is tapping into that mechanism.”

 

Zafgen researchers are investigating beloranib’s mechanism of action in patients that became very obese after their hypothalamus was damaged or removed as a result of craniopharyngioma, a type of brain cancer. “In about half of these cases, patients wake up hungry after surgery and it’s unrelenting, and they become morbidly obese very rapidly,” Kim says. Because the hypothalamus is damaged or missing, antiobesity drugs that target this brain region are ineffective. But beloranib “works just as well in these patients compared to patients with intact hypothalamus,” Kim says. As a result, beloranib may work in isolation without the need to combine different compounds, he adds. “If you can target a nodal point that’s much more upstream of simple circuitry-controlled hunger in the hypothalamus, you have the potential to reset the entire system.”

Meanwhile, another Boston-based firm, Rhythm Pharmaceuticals, is conducting clinical trials on obese patients with rare genetic disorders that compromise the melanocortin-4 (MC4) pathway, known to be involved in body weight regulation. Rhythm’s setmelanotide (RM-493) is a first-in-class drug that activates the MC4 pathway. And several companies, including the Japanese pharma firm Shionogi, are developing compounds that block the receptor of a neurotransmitter called neuropeptide Y, which plays a role in appetite stimulation and meal initiation.

Other new antiobesity targets include cyclic nucleotides, second messengers in signaling cascades such as the 3′-5′-cyclic guanosine monophosphate pathway, which conveys feelings of satiety and ramps up thermogenesis; amylin, a peptide hormone that slows gastric emptying and promotes satiety; ghrelin, a gut hormone that stimulates food intake; and a handful of pathways that affect nutrient absorption and metabolism. As more of obesity’s molecular complexities are sorted out, even more new drug targets will present themselves.

“I think we are on the verge of understanding obesity and the mechanisms underlying obesity,” says Novo Nordisk’s Thomsen. “That means that there is going to be a lot of good news for obesity going forward.”

 

WEIGHT-LOSS DRUG APPROVAL

© ISTOCK.COM/QUISP65Getting a weight-loss treatment approved by the FDA is a little different than the regulatory path taken by other drugs. To earn approval, companies must demonstrate that their drugs afford at least a 5 percent reduction in body weight over a year. And after a therapy reaches the market, companies have to conduct more research, specifically, into the drugs’ safety. Contrave, for example, which was approved in September 2014, is currently subject to rigorous post-marketing surveillance concerning evidence that the drug may lead to suicidal thoughts and behaviors. Other recently approved antiobesity drugs are under similar surveillance regimens.

The FDA also requires companies to test some approved weight-loss drugs specifically for their cardiovascular side effects. “Serious safety concerns have arisen with several obesity drugs in the past, which have informed our approach to drug development,” FDA spokesperson Eric Pahon wrote in an email to The Scientist. “All drugs approved for chronic weight management since 2012 have either had a cardiovascular outcome trial (CVOT) underway at the time of approval or have been required to initiate a CVOT as a post-marketing requirement.”

This additional testing, however, may scare off some drug developers from entering the antiobesity arena, Vivus spokesperson Dana Shinbaum wrote in an email to The Scientist. “The hurdles remain high . . . [and] may discourage innovation in this area.”

But even with the significant regulatory hurdles, it’s tough to deny the potential that exists in the antiobesity drug market. “We view obesity as one of the few remaining untapped therapeutic areas within primary care,” says Preston Klassen of Orexigen Therapeutics. “We think it’s tremendously important from a medical perspective, and we think it’s been well documented that even small reductions in body weight have meaningful and sustained impact on improved health.”

 

 

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Recent Insights in Drug Development

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

A Better Class of Cancer Drugs
http://www.technologynetworks.com/medchem/news.aspx?ID=183124
An SDSU chemist has developed a technique to identify potential cancer drugs that are less likely to produce side effects.
A class of therapeutic drugs known as protein kinase inhibitors has in the past decade become a powerful weapon in the fight against various life-threatening diseases, including certain types of leukemia, lung cancer, kidney cancer and squamous cell cancer of the head and neck. One problem with these drugs, however, is that they often inhibit many different targets, which can lead to side effects and complications in therapeutic use. A recent study by San Diego State University chemist Jeffrey Gustafson has identified a new technique for improving the selectivity of these drugs and possibly decreasing unwanted side effects in the future.

Why are protein kinase–inhibiting drugs so unpredictable? The answer lies in their molecular makeup.

Many of these drug candidates possess examples of a phenomenon known as atropisomerism. To understand what this is, it’s helpful to understand a bit of the chemistry at work. Molecules can come in different forms that have exactly the same chemical formula and even the same bonds, just arranged differently. The different arrangements are mirror images of each other, with a left-handed and a right-handed arrangement. The molecules’ “handedness” is referred to as chirality. Atropisomerism is a form of chirality that arises when the spatial arrangement has a rotatable bond called an axis of chirality. Picture two non-identical paper snowflakes tethered together by a rigid stick.

Some axes of chirality are rigid, while others can freely spin about their axis. In the latter case, this means that at any given time, you could have one of two different “versions” of the same molecule.

Watershed treatment

As the name suggests, kinase inhibitors interrupt the function of kinases—a particular type of enzyme—and effectively shut down the activity of proteins that contribute to cancer.

“Kinase inhibition has been a watershed for cancer treatment,” said Gustafson, who attended SDSU as an undergraduate before earning his Ph.D. in organic chemistry from Yale University, then working there as a National Institutes of Health poctdoctoral fellow in chemical biology.

“However, it’s really hard to inhibit a single kinase,” he explained. “The majority of compounds identified inhibit not just one but many kinases, and that can lead to a number of side effects.”

Many kinase inhibitors possess axes of chirality that are freely spinning. The problem is that because you can’t control which “arrangement” of the molecule is present at a given time, the unwanted version could have unintended consequences.

In practice, this means that when medicinal chemists discover a promising kinase inhibitor that exists as two interchanging arrangements, they actually have two different inhibitors. Each one can have quite different biological effects, and it’s difficult to know which version of the molecule actually targets the right protein.

“I think this has really been under-recognized in the field,” Gustafson said. “The field needs strategies to weed out these side effects.”

Applying the brakes

So that’s what Gustafson did in a recently published study. He and his colleagues synthesized atropisomeric compounds known to target a particular family of kinases known as tyrosine kinases. To some of these compounds, the researchers added a single chlorine atom which effectively served as a brake to keep the atropisomer from spinning around, locking the molecule into either a right-handed or a left-handed version.

When the researchers screened both the modified and unmodified versions against their target kinases, they found major differences in which kinases the different versions inhibited. The unmodified compound was like a shotgun blast, inhibiting a broad range of kinases. But the locked-in right-handed and left-handed versions were choosier.

“Just by locking them into one or another atropisomeric configuration, not only were they more selective, but they  inhibited different kinases,” Gustafson explained.

If drug makers incorporated this technique into their early drug discovery process, he said, it would help identify which version of an atropisomeric compound actually targets the kinase they want to target, cutting the potential for side effects and helping to usher drugs past strict regulatory hurdles and into the hands of waiting patients.

 

Inroads Against Leukaemia
http://www.technologynetworks.com/medchem/news.aspx?ID=183594

 

Potential for halting disease in molecule isolated from sea sponges.
A molecule isolated from sea sponges and later synthesized in the lab can halt the growth of cancerous cells and could open the door to a new treatment for leukemia, according to a team of Harvard researchers and other collaborators led by Matthew Shair, a professor of chemistry and chemical biology.

“Once we learned this molecule, named cortistatin A, was very potent and selective in terms of inhibiting the growth of AML [acute myeloid leukemia] cells, we tested it in mouse models of AML and found that it was as efficacious as any other molecule we had seen, without having deleterious effects,” Shair said. “This suggests we have identified a promising new therapeutic approach.”

It’s one that could be available to test in patients relatively soon.

“We synthesized cortistatin A and we are working to develop novel therapeutics based on it by optimizing its drug-like properties,” Shair said. “Given the dearth of effective treatments for AML, we recognize the importance of advancing it toward clinical trials as quickly as possible.”

The drug-development process generally takes years, but Shair’s lab is very close to having what is known as a development candidate that could be taken into late-stage preclinical development and then clinical trials. An industrial partner will be needed to push the technology along that path and toward regulatory approval. Harvard’s Office of Technology Development (OTD) is engaged in advanced discussions to that end.

The molecule works, Shair explained, by inhibiting a pair of nearly identical kinases, called CDK8 and CDK19, that his research indicates play a key role in the growth of AML cells.

The kinases operate as part of a poorly understood, massive structure in the nucleus of cells called the mediator complex, which acts as a bridge between transcription factors and transcriptional machinery. Inhibiting these two specific kinases, Shair and colleagues found, doesn’t shut down all transcription, but instead has gene-specific effects.

“We treated AML cells with cortistatin A and measured the effects on gene expression,” Shair said. “One of the first surprises was that it’s affecting a very small number of genes — we thought it might be in the thousands, but it’s in the low hundreds.”

When Shair, Henry Pelish, a senior research associate in chemistry and chemical biology, and then-Ph.D. student Brian Liau looked closely at which genes were affected, they discovered many were associated with DNA regulatory elements known as “super-enhancers.”

“Humans have about 220 different types of cells in their body — they all have the same genome, but they have to form things like skin and bone and liver cells,” Shair explained. “In all cells, there are a relatively small number of DNA regulatory elements, called super-enhancers. These super-enhancers drive high expression of genes, many of which dictate cellular identity. A big part of cancer is a situation where that identity is lost, and the cells become poorly differentiated and are stuck in an almost stem-cell-like state.”

While a few potential cancer treatments have attacked the disease by down-regulating such cellular identity genes, Shair and colleagues were surprised to find that their molecule actually turned up the activity of those genes in AML cells.

“Before this paper, the thought was that cancer is ramping these genes up, keeping the cells in a hyper-proliferative state and affecting cell growth in that way,” Shair said. “But our molecule is saying that’s one part of the story, and in addition cancer is keeping the dosage of these genes in a narrow range. If it’s too low, the cells die. If they are pushed too high, as with cortistatin A, they return to their normal identity and stop growing.”

Shair’s lab became interested in the molecule several years ago, shortly after it was first isolated and described by other researchers. Early studies suggested it appeared to inhibit just a handful of kinases.

“We tested approximately 400 kinases, and found that it inhibits only CDK8 and CDK19 in cells, which makes it among the most selective kinase inhibitors identified to date,” Shair said. “Having compounds that precisely hit a specific target, like cortistatin A, can help reduce side effects and increase efficacy. In a way, it shatters a dogma because we thought it wasn’t possible for a molecule to be this selective and bind in a site common to all 500 human kinases, but this molecule does it, and it does it because of its 3-D structure. What’s interesting is that most kinase-inhibitor drugs do not have this type of 3-D structure. Nature is telling us that one way to achieve this level of specificity is to make molecules more like cortistatin A.”

Shair’s team successfully synthesized the molecule, which helped them study how it worked and why it affected the growth of a very specific type of cell. Later on, with funding and drug-development expertise provided by Harvard’s Blavatnik Biomedical Accelerator, Shair’s lab created a range of new molecules that may be better suited to clinical application.

“It’s a complex process to make [cortistatin A] — 32 chemical steps,” said Shair. “But we have been able to find less complex structures that act just like the natural compound, with better drug-like properties, and they can be made on a large scale and in about half as many steps.”

“Over the course of several years, we have watched this research progress from an intriguing discovery to a highly promising development candidate,” said Isaac Kohlberg, senior associate provost and chief technology development officer. “The latest results are a real testament to Matt’s ingenuity and dedication to addressing a very tough disease.”

While there is still much work to be done — in particular, to better understand how CDK8 and CDK19 regulate gene expression — the early results have been dramatic.

“This is the kind of thing you do science for,” Shair said, “the idea that once every 10 or 20 years you might find something this interesting, that sheds new light on important, difficult problems. This gives us an opportunity to generate a new understanding of cancer and also develop new therapeutics to treat it. We’re very excited and curious to see where it goes.”

 

Seeking A Better Way To Design Drugs

http://www.technologynetworks.com/medchem/news.aspx?ID=183338

NIH funds research at Worcester Polytechnic Institute to advance a new chemical process for more effective drug development and manufacturing.
The National Institutes of Health (NIH) has awarded $346,000 to Worcester Polytechnic Institute (WPI) for a three-year research project to advance development of a chemical process that could significantly improve the ability to design new pharmaceuticals and streamline the manufacturing of existing drugs.

Led by Marion Emmert, PhD, assistant professor of chemistry and biochemistry at WPI, the research program involves early-stage technology developed in her lab that may yield a more efficient and predictable method of bonding a vital class of structures called aromatic and benzylic amines to a drug molecule.

“Seven of the top 10 pharmaceuticals in use today have these substructures, because they are so effective at creating a biologically active compound,” Emmert said. “The current processes used to add these groups are indirect and not very efficient. So we asked ourselves, can we do it better? ”

For a drug to do its job in the body it must interact with a specific biological target and produce a therapeutic effect. First, the drug needs to physically attach or “bind” to the target, which is a specific part of a cell, protein, or molecule. As a result, designing a new drug is like crafting a three-dimensional jigsaw puzzle piece that fits precisely into an existing biological structure in the body. Aromatic and benzylic amines add properties to the drug that help it bind more efficiently to these biological structures.

Getting those aromatic and benzylic amines into the structure of a drug, however, is difficult. Traditionally, this requires a specialized chemical bond as precursor in a specific location of the drug’s molecular structure. “The current approach to making those bonds is indirect, requires several lengthy steps, and the outcome is not always precise or efficient,” Emmert said. “Only a small percentage of the bonds can be made in the proper place, and sometimes none at all.”

Emmert’s new approach uses novel reagents and metal catalysts to create a process that can attach amines directly, in the right place, every time. In early proof-of-principle experiments, Emmert has succeeded in making several amine bonds directly in one or two days, whereas the standard process can take two weeks with less accuracy. Over the next three years, with support from the NIH, Emmert’s team will continue to study the new catalytic processes in detail. They will also use the new process to synthesize Asacol, a common drug now in use for ulcerative colitis, and expect to significantly shorten its production.

“Some of our early data are promising, but we have a lot more work to do to understand the basic mechanisms involved in the new processes,” Emmert said. “We also have to adapt the process to molecules that could be used directly for drug development.”

 

Antiparasite Drug Developers Win Nobel

William Campbell, Satoshi Omura, and Youyou Tu have won this year’s Nobel Prize in Physiology or Medicine in recognition of their contributions to antiparasitic drug development.

By Karen Zusi and Tracy Vence | October 5, 2015

http://www.the-scientist.com//?articles.view/articleNo/44159/title/Antiparasite-Drug-Developers-Win-Nobel/

William Campbell, Satoshi Omura, and Youyou Tu have made significant contributions to treatments for river blindness, lymphatic filariasis, and malaria; today (October 5) these three scientists were jointly awarded the 2015 Nobel Prize in Physiology or Medicine in recognition of these advancements.

Tu is being recognized for her discoveries leading to the development of the antimalarial drug artemisinin. Campbell and Omura jointly received the other half of this year’s prize for their separate work leading to the discovery of the drug avermectin, which has been used to develop therapies for river blindness and lymphatic filariasis.

“These discoveries are now more than 30 years old,” David Conway, a professor of biology of the London School of Hygiene & Tropical Medicine, told The Scientist. “[These drugs] are still, today, the best two groups of compounds for antimalarial use, on the one hand, and antinematode worms and filariasis on the other.”

Omura, a Japanese microbiologist at Kitasato University in Tokyo, isolated strains of the soil bacteriaStreptomyces in a search for those with promising antibacterial activity. He eventually narrowed thousands of cultures down to 50.

Now research fellow emeritus at Drew University in New Jersey, Campbell spent much of his career at Merck, where he discovered effective antiparasitic properties in one of Omura’s cultures and purified the relevant compounds into avermectin (later refined into ivermectin).

“Bill Campbell is a wonderful scientist, a wonderful man, and a great mentor for undergraduate students,” said his colleague Roger Knowles, a professor of biology at Drew University. “His ability to speak about disease mechanisms and novel strategies to help [fight] these diseases. . . . that’s been a great boon to students.”

Tu began searching for a novel malaria treatment in the 1960s in traditional herbal medicine. She served as the head of Project 523, a program at the China Academy of Chinese Medical Sciences in Beijing aimed at finding new drugs for malaria. Tu successfully extracted a promising compound from the plant Artemisia annu that was highly effective against the malaria parasite. In recognition of her malaria research, Tu won a Lasker Award in 2011.

 

Optogenetics Advances in Monkeys

Researchers have selectively activated a specific neural pathway to manipulate a primate’s behavior.

By Kerry Grens | October 5, 2015

http://www.the-scientist.com//?articles.view/articleNo/44156/title/Optogenetics-Advances-in-Monkeys/

Scientists have used optogenetics to target a specific neural pathway in the brain of a macaque monkey and alter the animal’s behavior. As the authors reported in Nature Communications last month, such a feat had been accomplished only in rodents before.

Optogenetics relies on the insertion of a gene for a light-sensitive ion channel. When present in neurons, the channel can turn on or off the activity of a neuron, depending on the flavor of the channel. Previous attempts to use optogenetics in nonhuman primates affected brain regions more generally, rather than particular neural circuits. In this case, Masayuki Matsumoto of Kyoto University and colleagues delivered the channel’s gene specifically to one area of the monkey’s brain called the frontal eye field.

They found that not only did the neurons in this region respond to light shone on the brain, but the monkey’s behavior changed as well. The stimulation caused saccades—quick eye movements. “Our findings clearly demonstrate the causal relationship between the signals transmitted through the FEF-SC [frontal eye field-superior colliculus] pathway and saccadic eye movements,” Matsumoto and his colleagues wrote in their report.

“Over the decades, electrical microstimulation and pharmacological manipulation techniques have been used as tools to modulate neuronal activity in various brain regions, permitting investigators to establish causal links between neuronal activity and behaviours,” they continued. “These methodologies, however, cannot selectively target the activity (that is, the transmitted signal) of a particular pathway connecting two regions. The advent of pathway-selective optogenetic approaches has enabled investigators to overcome this issue in rodents and now, as we have demonstrated, in nonhuman primates.”

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