KRAS(G12C) Inhibitors: Shatter the myth about Undruggable Mutation Oncogene

For over 30 years, the protein KRAS is a major challenge in drug design. So far, there is no approved therapy for patients with KRAS mutations, which comprise around 25% of patients with lung cancer. It’s been on everyone’s “target” list as commonly mutated oncogene, while KRAS has earned a reputation in scientific circles as being “undruggable” because many pharmaceutical, biotech, and academic laboratories have failed to design a drug that successfully targets the mutant gene.

The KRAS Pathway and chemical compounds sitting inside a pocket in KRAS. The KRAS Pathway and chemical compounds sitting inside a pocket in KRAS.

But recently , Dr. Kevan M. Shokat and his colleagues, in the Howard Hughes Medical Institute (HHMI) at the University of California, published an article entitled “KRAS(G12C) inhibitors allosterically control GTP affinity and effector interactions ” in the Nature journal, which aims for identifying and exploiting a novel “Achilles heel” in KRAs. They found “pocket”, or binding site, and designed a chemical compound that fits inside this pocket and inhibits the normal activity of mutant KRAS.

The above small molecules irreversibly bind to KRAS(G12C), subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Shokat said, “We report the discovery of a new pocket on KRAS that is druggable, and we believe this has real translational implications for patients.”

 Additionally, Dr. Nathanael S. Gray, in the Department of Cancer Biology at the Dana-Farber Cancer Institute, reported the synthesis of a GDP analogue(SML-8-73-1) and a prodrug derivative (SML-10-70-1), which were selective, direct-acting covalent inhibitors of the KRAS (G12C) mutant relative to wild-type Ras. Biochemical and biophysical measurements suggested that modification of KRAS with SML-8-73-1 renders the protein in an inactive state.

What is KRAS protein?

KRAS, a member of Ras protein family, acts as a molecular on/off switch. When turned on , it recruits and activates proteins necessary for the proliferation of growth factor and ther receptors’ signal such as c-Raf and PI 3-kinase. In Combination with GTP, KRAS possesses an intrinsic enzymatic activity which cleaves the terminal phosphate of the nucleotide, and finally make itself turn off.

KRAS is one of the most frequently mutated oncogenes in human cancer. According to a discovery nearly 30 years ago, KRAS is mutated in 30 percent of human tumors, including 90 percent of pancreatic cancers, 40 percent of colon cancers, and 20 percent of non-small cell lung cancers. Cancers with Ras mutations are aggressive and respond poorly to standard therapies.

How to test KRAS mutations

KRAS mutations (adapted from Heinemann et al.,2009) KRAS mutations (adapted from Heinemann et al.,2009)

The usual testing detects the seven common mutations in exon 2, codons 12 and 13, which account for up to 90-95% of KRAS gene mutations. While scientists would use variant methods without standardized regulations. It is noteworthy that Mayo Clinic’s Molecular Genetics Laboratory has recently introduced a KRAS mutation analysis assay (#89378 KRAS Gene, 7 Mutation Panel, Tumor Tissue) that tests for the common mutations in codons 12 and 13. As shown in the assay, concordance between the presence or absence of KRAS mutations in a patient’s primary tumor and corresponding metastatic tumors is high.

KRAS mutation testing may be performed on the primary tumor or a metastasis, and both are equally acceptable. The pathologist should select a tissue sample that is predominantly tumor and estimate the percentage of tumor cells in the sample. After all, direct sequencing, generally considered as the “gold standard” for KRAS mutation detection, requires a higher percentage of tumor DNA to reliably detect the mutation.

 Treatment for cancer patients with KRAS Mutation

The Selected 4 Trials for KRAS Mutation The Selected 4 Trials for KRAS Mutation

Some clinical trial data has suggested that patients with a KRAS mutation treated with chemotherapy and anti-EGFR therapy not only did not respond to the treatment, but had worse clinical outcomes than those treated with chemotherapy alone. There is currently no clear explanation for these findings.

Recent studies indicate that KRAS-normal tumors with a BRAF V600E mutation will also not respond to EGFR targeted therapy. This prompted National Comprehensive Cancer Network (NCCN) to update their guidelines to include optional BRAF mutation testing if KRAS results are normal.

EGFR is a therapeutic target for several other human tumors and Erbitux has been approved for use in certain head and neck cancers. However, KRAS mutation testing is not routinely recommended to guide treatment decisions for any other cancers.

References:

1. KRAS(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature.  2013, 503, 548–551

2. Therapeutic Targeting of Oncogenic KRAS by a Covalent Catalytic Site Inhibitor. Angew Chem Int Ed Engl. 2014 Jan 3;53(1):199-204.

3. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treatment Reviews. 2009,

35(3):262-271

Capture of Culprit mutations for Targeted Therapies

As the rocketing development of sequencing techniques, oncogene discovery enters an era of exponential growth, which supports many therapeutic targets for certain types of cancer. The statistical data reported is that 78% of cancer patients have one or more “culprit” mutations. Thus, establishing The pathogentic relevance of individual mutations is a major challenge to be solved.

Scientists can figure out the genetic rules of cancer in the support of diagnosis, risk stratification and individualized treatment, after large-scale cancer genomes have been sequenced. “We’re finding clinically relevant information in the tumor samples we’re sequencing for discovery-oriented research,” says Elaine Mardis, PhD, co-director of the Genome Institute at the School of Medicine. “Genome analysis can play a role at multiple time points during a patient’s treatment, to identify culprit mutations in the tumor genome and to determine whether cells carrying those mutations have been eliminated by treatment.”

Identify “Culprit” Genes for Cancer Treatment

Information of cancer genomes has been screened to identify specific culprit genes, which determine patients’ response to drug. In patients with advanced lung cancer, TORCH (Tarceva or Chemotherapy) investigators have found culprit mutations in EGFR that can be targeted by Erlotinib.

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Additionally, Mardis has also found numerous culprit mutations in genes that have not previously been associated with breast tumors. A number of these genes have been identified in prostate, colorectal, lung or skin cancer, and leukemia. Drugs that target mutations in these genes, including imatinib, ruxolitinib and sunitinib, are already on the market.

Optimize Treatment

A series of mutations in the breast tumors, screened by GWAS strategies, have small-molecule inhibitor drugs that target defective proteins. For patients who are not responding to aromatase inhibitors, treatment options may encompass adding the indicated small-molecule inhibitor into conventional chemotherapy.

“We felt it was important to show that there could be therapeutic options available to patients who are resistant to aromatase inhibitors,” says PhD Mardis,. “As we move forward, we think sequencing will contribute crucial information to determining the best treatment options for patients.”

Reference:

The Next-Generation Sequencing Revolution and Its Impact on Genomics. Cell 2013;

155(1): 27–38

Track Landmarks in Cancer

For over a century, scientists have been exploring the mechanisms of cancer growth and spread, which deepen our understanding of cancer from molecular and cellular perspectives. Some landmark discoveries are picked out in the support of advisors, based on the context of the prevailing concepts and current knowledge. Special supplements released on the Nature website cover these landmarks, including a Timeline of the earliest papers.

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Review-type articles in cancer

Nature Publishing Group (NPG) library contains research and review-type articles on the topic of cancer from 9 journals, such as Nature, Nature Medicine, and Nature Reviews Cancer. To introduce cancer research of landmark significance, Special supplements highlight 3 articles of review listed as follows.

Dr. Scott W at Cold Spring harbor laboratory, New York, published an article entitled ” Intrinsic tumour suppression” in the Nature journal. “Evolution installs in the proliferative programmes of mammalian cells a variety of innate tumour-suppressive mechanisms that trigger apoptosis or senescence. These contingent processes rely on a series of sensors and transducers that act in a coordinated network to target the machinery responsible for apoptosis and cell-cycle arrest at different points ” mentioned Scott. “Although oncogenic mutations that disable such networks can have profound and varied effects on tumour evolution, they may leave intact latent tumour-suppressive potential that can be harnessed therapeutically. “

DR. Vogelstein B in Howard Hughes medical institute, issued a review of “cancer genes and the pathways they control ” in the Nature Medicine journal. “The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease.” described Vogelstein, ” In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.”

Dr. Bruce A. Chabner in the division of hematology/oncology, Massachusetts General Hospital, published an article with title of “Chemotherapy and the war on cancer” in the Nature Reviews Cancer journal. ” The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards and antifolate drugs” wrote Bruce, ” Cancer drug development since then has transformed from a low-budget, government-supported research effort to a high-stakes, multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply. This article chronicles the history of modern chemotherapy and identifies remaining challenges for the next generation of researchers. “

References:

1. Intrinsic tumour suppression. Nature 2004. 432, 307−315

2. Cancer genes and the pathways they control. Nature Medicine 2004. 10, 789−799

3 Chemotherapy and the war on cancer. Nature Reviews Cancer 2005. 5, 65−72

Possibility of using bio- signatures to define patient subsets to benefit from immunotherapy

Tremelimumab, formerly ticilimumab, is a fully human IgG2 monoclonal antibody produced by Pfizer, undergoing human trials for the treatment of cancer.Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism that interrupts this destruction. Tremelimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.

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Tremelimumab binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing of cancer cells. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated down-regulation of T-cell activation; subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition.Tremelimumab stimulates patients’ immune systems to attack their tumors. It has induced durable tumor responses in patients with metastatic melanoma in Phase 1 and Phase 2 clinical studies.On April 2, 2008, Pfizer announced that it has discontinued a Phase III clinical trial for patients with advanced melanoma after the review of interim data showed that the trial would not demonstrate superiority to standard chemotherapy.

Recently, pretreatment peripheral blood samples from 218 patients with melanoma who were refractory to prior therapy and receiving tremelimumab in a multicenter phase II study were measured for 169 mRNA transcripts using reverse transcription polymerase chain reaction (RT-PCR).A two-class latent model yielded a risk score based on four genes that were highly predictive of survival(P < 0.001). This signature was validated in an independent population of 260 treatment-naive patients with melanoma enrolled in a multicenter phase III study of tremelimumab.

Results have showed that expression levels of the 169 genes were closely correlated across the two populations. A four-gene model, including cathepsin D(CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1(TXNRD1), and interleukin 1 receptor–associated kinase 3 (IRAK3), predicted survival in the test population. Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in patients with melanoma treated with tremelimumab. Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.

Reference:

Blood mRNA Expression Profiling Predicts Survival in Patients Treated with Tremelimumab. Clinical Cancer Research. 2014;1-9.

Why has cancer drug discovery changed so much?

Cancer drug discovery has undergone a remarkable series of changes over the last 15 years. So what has changed so much?

First, the molecular targets of contemporary cancer drug discovery projects are very different. Current targets reflect our increasing understanding of the genetic and epigenetic changes that are responsible for the initiation and malignant progression of cancer through the dysregulation of cell biochemistry and signaling networks.

Second, the integrated application of a range of powerful drug discovery technologies has had

a major impact .

Third, many new treatments have emerged over the last 15 years based on this paradigm that are firmly established in the clinic. The present volume brings together many of the important aspects of the discovery and design of new cancer drugs, emphasizing small molecules.

Integrated small-molecule drug discovery and development

The successful discovery and development of small-molecule cancer drugs are highly dependent upon the creative interplay between many disciplines: these include genetics, genomics, and bioinformatics; cell and molecular biology; structural biology; tumor biology; pharmacology; pharmacokinetics and metabolism; medicinal chemistry; and experimental medicine. The application of a wide range of powerful technologies has had a major impact.

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New molecular targets: the druggable cancer genome and epigenome

The selection of the best possible molecular targets is clearly crucial to the success of a drug discovery and development project. A number of factors influence the choice of target, including, in particular, (1) the involvement of the target in the initiation and progression of cancer, and (2) the technical feasibility or “druggability” of the target. With the mapping of the human genome sequence, the concept of the “druggable genome” has become popular and useful.

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Reference:

Modern Cancer Drug Discovery: Integrating Targets, Technologies, and Treatments for Personalized Medicine. Cancer Drug Design and Discovery (Second Edition). 2014; 3-53.

MicroRNA could be valuable biomarkers for prostate cancer detection and management

Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may spread from the prostate to other parts of the body, particularly the bones and lymph nodes. Prostate cancer may initially cause no symptoms, but in later stages can cause pain, difficulty in urinating, problems during sexual intercourse, erectile dysfunction, and death. Other symptoms can potentially develop during later stages of the disease.

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Prostate cancer is most common in the developed world with increasing rates in the developing world. However, many men with prostate cancer never have symptoms, undergo no therapy, and eventually die of other unrelated causes.

Some research using microarray showed that microRNA-224 (miR-224) was down-regulated in human prostate cancer tissues compared with adjacent benign tissues. However, the underlying mechanisms by which miR-224 is involved in prostate cancer remain unclear. Through further research, scientists identified TRIB1 as a target gene of miR-224. Forced expression of miR-224 suppressed prostate cancer cell proliferation, invasion and migration, and promoted cell apoptosis by down-regulating TRIB1.

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Moreover, the expression level of miR-224 in prostate cancer tissues was negatively correlated with that of TRIB1. Down-regulation of miR-224 was frequently found in prostate cancer tissues with metastasis, higher PSA level and clinical stage, whereas TRIB1 up-regulation was significantly associated with metastasis. Both miR-224 down-regulation and TRIB1 up-regulation were significantly associated with poor biochemical recurrence-free survival of patients with prostate cancer. In conclusion, these findings reveal that the aberrant expression of miR-224 and TRIB1 may promote Prostate cancer progression and have potentials to serve as novel biomarkers for Prostate cancer prognosis.

Reference:

MicroRNA-224 inhibits progression of human prostate cancer by downregulating TRIB1. International Journal of Cancer. 2014; 135: 541–550.

Unveil a Novel Mechanism for Bleomycin against Cancer

Approved by FDA in 1973, bleomycin– an kind of antibiotic produced by the bacterium, Streptomyces verticillus — has been employed for clinical treatment, especially for Hodgkin’s lymphoma, squamous cell carcinomas, and testicular cancer. However, its anti-cancer mechanism remain poorly known.

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In a new research, investigators depict bleomycin’s property to cut through double-stranded DNA in cancerous cells, like a pair of scissors. Such DNA cleavage always cause some types of cancer to death. The study, lead by Basab Roy, firstly present alternative biochemical mechanisms for DNA cleavage by bleomycin.

Specifically bind DNA regions

Scientists keep on studying several forms of bleomycin and developing a scaled library of variants, with the purpose of designing the best bleomycin analog. Their interests focus on the subtle biochemistry of bleomycin, including the specificity of its binding sites along the DNA strand and the drug ‘s detailed mechanisms of DNA cleavage.

Beomycin A5 in the new study has similar DNA binding and cleaving properties, as well as bleomycin A2 and B2. Previous research has revealed that bleomycin binds with highly specific regions of the DNA strand, typically G-C sites, where a guanosine base pairs with a cytidine. Further, the strength of this binding is closely associated with the degree of double-strand DNA cleavage.

Cut cancer to pieces

As one of attractive feature, Bleomycin can be administered in relatively low doses in the treatment of some many other cancer. Previous research has shown that bleomycin can cause death in aberrant cells by migrating to the cell nucleus, binding with DNA and subsequently causing breaks in the DNA sequence.

Cleavage of DNA is regarded as a major mechanism by which bleomycin kills cancer cells, particularly through double-strand cleavages. It pose a great challenging for the cellular machine to repair. “There are several mechanisms for repairing both single-strand and double-strand breaks in DNA, but double-strand breaks are a more potent form of DNA lesion,” Roy says.

There is a great deal of work required to elucidate the biochemical causes of tight binding by bleomycin. The future discovery on drug-DNA binding aspect will guide improvement of the drug in property and alleviation of toxicity to healthy cells.

References:

1. Hairpin DNA Sequences Bound Strongly by Bleomycin Exhibit Enhanced Double-Strand Cleavage. Journal of the American Chemical Society, 2014; 136 (11): 4382

2. Targeting DNA damage and repair: Embracing the pharmacological era for successful cancer therapy. Pharmacol Ther. 2012 Mar;133(3):334-50.

Escape the Risk of Infertility for Young Survivors after Cancer Treatment

A person’s fertility during and after a cancer diagnosis is associated with cancer survivorship, especially for those patients younger than 30 years. With long-term survival rates, they will inevitably face reproductive issues because some types of cancer treatments, such as chemotherapy and radiation therapy, may cause temporary or permanent infertility.

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Influence of cancer treatment on fertility

If a female cancer survivor want to conceive spontaneously, she will require sufficient ovarian follicular reserve, a uterus that supports a developing fetus, and functional organ systems. While cancer and related treatments can potentially disrupt any aspect of this delicate balance and limit a patient’s reproductive potential.

Treatment-related infertility is reported to be significantly related with survivors’ quality of life. For some patients, physical changes make it more difficult to conceive a child, even leading to a complete, permanent loss of fertility. Thus younger cancer patients struggle to identify themselves as normal, or the potential for future fertility, and then feel relaxed. In this context, a fertility preservation consultation may be a source of hope.

Tackle fertility issue

Appropriate patients are referred to fertility specialists for further counseling and fertility preservation. The standard practice investigators take is the cryopreservation of sperm, oocyte, and embryo according to existing guidelines. Since a decline in vitro fertilization (IVF) outcomes following cancer treatment is well documented, it is imperative to the success of fertility preservation that embryos or oocytes are preserved prior to the initiation of cancer treatment.

Both embryos or oocytes cryopreservation require the use of IVF, which enables patients to potentially take advantage of preimplantation genetic diagnosis (PGD), a method of screening embryos or oocytes for genetic abnormalities before transfer into the uterus. While most cancers arise sporadically, 5% to 10% of cancer diagnoses are inherited through currently recognized genetic cancer syndromes.

Hereditary Cancer Syndromes for Which PGD Has Been Used to Identify Affected Embryos

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References :

1. Fertility issues in cancer survivorship. CA: A Cancer Journal for Clinicians. 2014; 64( 2):118–134

2. Highly penetrant hereditary cancer syndromes. Oncogene. 2004;23:6445-6470.

Disclose the Action Film of Invasive Tumour Cells

Mikala Egeblad observed the action film of tumour cells by recording their landscapes inside live mice. In the previous study, cells stayed still, frozen on microscope slides, but now viewing them in a living animal brings cells to life. “You turn on the microscope and look in the live mouse and suddenly these same cells are running around like crazy,” says Egeblad, a cancer researcher at Cold Spring Harbor Laboratory in New York. “It really changed my thinking.”

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Novel technique offer the chance to spy on the action of individual tumour cells, and investigators thereby utilize relative clues to hypothesis about how cancers grow ,spread and resist treatment. As an promising approach, Tracking Cancer in Live Animals over Time(TCLAT, also called intravital imaging) allows biologists to piece together timelines for key cellular and molecular events, and zoom in some lesion cells that drive the disease or resist treatment.

Intravital imaging involves focusing powerful microscopes directly onto exposed tissue in a live mouse. Microscopy technology, In combination with markers, make this approach powerful. A growing library of molecular makers are available to enhance the color identification and enable researchers to visualize different types of cells and structure, such as immune-system cells.

Recording cancer response to drug

Some scientists are using intravital imaging to track cancer drugs in the body, and to explore why some drug treatments fail. Cancer biologists typically test the effect of chemotherapies in vivo by measuring changes in cancer growth and size in mice. Intravital imaging gives a more direct view, revealing which cells in a lesion take up the drugs, and whether those cells live or die.

Egeblad and her team have made films of doxorubicin, a naturally fluorescent cancer drug, as it infiltrated mammary tumours in mice. They were surprised by the degree of variability — even within small regions of the tumour — in the amount of the drug that got into the cells, and in the number of cells that died.

Viewing action film of tumour cells help aware that the microenvironment, not just genetics, can influence cancer. The further study is an opportunity to reply the questions with deep and  broad insights: how do different components of the tumour and its environment co-evolve?

References:

1. Intravital microscopy through an abdominal imaging window reveals a pre-micrometastasis stage during liver metastasis. Sci Transl Med. 2012 Oct 31;4(158):158ra145.

2. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res. 2009 Apr 1;15(7):2433-41.

Big Pharma’s Thirst for Anticancer Drugs Speeds Up Pharma Industry Reshaping

High investments in oncology not surely bring about novel drugs, however pharma still focus R&D on anticancer drugs. It is promising for anticancer drugs to be rewarded with high economic returns, as the top ten best-selling antibody therapeutics for cancer have accumulated revenues approaching $200 Billion.

Source: IMS MEDAS MAT September 2010 *Oncology defines as L1+L2 and limited to ethnical, none-generic Source: IMS MEDAS MAT September 2010 *Oncology defines as L1+L2 and limited to ethnical, none-generic

Nowadays, Roche keeps a dominated market share in the anticancer drug, involving three types of blockbuster drug(MabThera, Avastin, and Herceptin) ranked in top 3 of best -selling anticancer drugs in 2013. While its rivals, including Novartis and Pfizer, intend to enhance the competitive power through integration and merger, which inevitably result in pharma industry reshaping.

Roche take the lead in cancer drug

Roche is the largest producer of anti-cancer drugs. In the 2013 financial year, Roche generated sales of around CHF 46.8 billion (approximately $ 52.7 billion)and net profit of CHF 11.2 billion(approximately $ 12.6 billion).

Additionally, Roche has achieved a great success in the anticancer drug development, where some novel drug recently get approved to enrich its product pipeline. In 2012, the antibody pertuzumab (Roche) which inhibits the dimerization of HER2 and HER3 receptors was approved for HER2 metastatic breast cancer. In 2013, Roche saw the approval of trastuzumab emtansine for the same indication. This antibody-drug conjugate consists of the monoclonal antibody trastuzumab linked to the cytotoxic agent mertansine. Another approval for Roche in 2013 was that of vismodegib, the first-in-class hedgehog pathway inhibitor, which was approved for the treatment of basal cell carcinoma (BCC).

Novartis obtains takeover of GSK ‘s anticancer drug division

Swiss firm Novartis is selling its animal medicines division and swapping assets with Britain’s GlaxoSmithKline. It means GSK will no longer make anti-cancer drugs and it will acquire Novartis’ vaccines division.

Mike Ingram, Market Analyst, BGC Partners said: “It’s positive news for shareholders, clearly what’s going on in terms of the big picture is these pharma companies are trying to rationalise their portfolios, they’re trying to do less, better. Scale, critical mass and better pipeline are absolutely important.”

Pfizer chases AstraZeneca for immunotherapy drugs against cancer

U.S. drugmaker Pfizer Inc approaches Britain’s AstraZeneca Plc to reignite a potential $100 billion takeover, raising investor expectations it will have to increase its offer to close the deal.

AstraZeneca has a very good pipeline of immunotherapy drugs, which was what attracted Pfizer. For example, its immunotherapy compound MEI4736 has recently advanced into phase-III clinical trials (the testing stage before launch).

Buying AstraZeneca would boost Pfizer’s pipeline of cancer drugs and create significant cost and tax savings. Under British takeover rules, Pfizer has until May 26 to announce a firm intention to make an offer or back away.