Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘Landscape Opportunity’ category

KRAS mutations in colorectal cancer may determine therapy options

By on June 2, 2008

Kras
KRAS mutation status has recently been shown to relate to outcome in metastatic colorectal (mCRC) patients treated with cetuximab as a single agent or in combination with irinotecan.  Efficacy analyses have been repeated to evaluate the influence of KRAS mutation status in first-line pts treated with FOLFIRI with or without ImClone's Erbitux (cetuximab) under controlled study conditions.  A normal KRAS gene sends a signal telling cells to divide.
The mutation is associated with uncontrolled division of tumour
cells, ie no apoptosis or programmed cell death occurs.

For most people with a normal version of the gene, known as
KRAS, adding Erbitux to chemotherapy slashed the risk
of the disease progressing by a third, according to a study presented at the annual meeting of the American Society of
Clinical Oncology in Chicago. 

In the Erbitux study, researchers examined tissue samples
from 587 patients getting initial treatment for advanced
colorectal cancer.  About 59 percent of those with normal KRAS
responded to Erbitux plus chemotherapy, compared with 43 percent
of those who took chemotherapy alone.  Adding Erbitux didn't harm
patients carrying the mutation, though it offered no benefit.

This means that KRAS testing may end up being routinely conducted in all
colorectal cancer patients immediately after diagnosis in order to determine which targeted therapy is most suitable for patients.  Focusing EGFR treatment on the normal KRAS patients (approx. 60%) may result in a much bigger benefit, which
is clinically very important.  Clearly, there is no point in treating the 40% of the patients who do have the KRAS mutation with a drug that is unlikely to work.

Meanwhile, another EGFR inhibitor, Amgen's Vectibix (panitumumab), also wasn't effective for patients with a
KRAS mutation in a similar study presented at a cancer meeting
in January.  The drug slowed the spread of tumors for 12.3 weeks
in patients with a normal gene, compared with 7.4 weeks in those
with the mutation.

Almost 150,000 people in the U.S. will be diagnosed with
colorectal cancer in 2008, according to the American Cancer
Society.  The ability to choose a drug based on a genetic target
can help doctors treat the disease more effectively and may change the way Erbitux
competes against Genentech's Avastin,
which had sales of $3.4 billion last year.

Sources:

Photo: Boulard, Y. Cognet, J.A. Fazakerley, G.V., J. Mol. Biol.
268 (1997) 331-347.


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New treatments for renal cell cancer

By on April 22, 2006

Often cancer can be traced back to a translocation e.g. blood cancers such as leukemias or a gene addition/subtraction as found with many solid tumours such as breast cancer.

It has been known that kidney or renal cell cancer is linked to the Von Hippel Lindau (VHL) gene, where the tumour develops when the gene is faulty. A normal VHL gene usually protects against developing cancer.

Renal_cell_cancer

Approximately 30,000 people are affected by renal cancer in Europe and the United States. Recently, two new drugs were approved in the US which are regulated by other pathways associated with this gene. One was Nexavar from Bayer and the other Sutent from Pfizer. Response rates of 20-30% were typically seen, which although low, is still promising compared to standard therapy such as IL-2 and interferon-alpha with more tolerable side effects. Screening patients for defects in the VHL gene may lead to higher response rates and survival using a more targeted approach to patient selection.

Click Here for more information on the mutant VHL gene news.

Other therapeutic approaches to the treatment of renal cancer are also being considered including m-Tor inhibitors such as temsirolimus (Torisel) from Wyeth. This agent induces apoptosis and reduces cell proliferation and may offer an exciting new approach to the treatment of the disease. Novartis also a potent mTor inhibitor in development called Afinitor (RAD001, everolimus), which is expected to be available in 2009 in the US.

Ultimately, the optimal treatment may include a multi-faceted approach whereby different drugs can be used in sequence or in combination to attack different pathways associated with the disease, increasing chances of success and reducing to opportunities for drug resistance to develop.

New data will likely be available at the American Society of Clinical Oncology meeting in June; let’s hope it is promising!

Aurora kinase inhibitors: new class of cancer treatment?

By on March 3, 2006

Aurora kinases are key regulators of cell division and proliferation; the enzyme helps the dividing cell share its genetic material with the daughter cells. There are 3 different classes, A, B and C. Over expression of aurora kinase has been associated with several different cancers including breast, colon, bladder, pancreatic, ovarian and leukemia. Indeed, over expression of aurora kinase A has been linked to poor prognosis in breast cancer.

It is not yet known whether the pathway is critical to aberrant signaling, although inhibition has been shown to slow the uncontrolled cell growth that characterizes cancer. Aurora kinases do, however, appear to map to chromosome regions that are frequently altered in tumours. In preclinical models, over expression leads to aggressive tumour growth and resistance to cytotoxic agents.

The concept of aurora kinase inhibitors is, therefore, an avenue well worth researching as a potential new class of anti-cancer agents. Preclinically, some of the initial prototypes have been shown to block the final stages of cell division, resulting in apoptosis and cancer cell death.

Three of the leading aurora kinase inhibitors in early testing at the moment are from Vertex (VX-680), Riga (R-763) and Millennium (MLN-8054). Interestingly, both the Vertex and Riga compounds have been licensed out to Merck and Serono, for deals of $350M and $160M, respectively. There are a number of other agents in preclinical development at AstraZeneca, Sunesis, Entremed, Boehringer Ingelheim, Cyclacel and others, so the field is a busy and active one, competition wise.

It will be interesting to follow the development of this new class of agents and see whether the concept lives up to the promise. At the recent AACR meeting in Philadelphia there were a number of abstracts on aurora kinases and there will be surely more to come at the 2006 annual meeting in April (click here).

Watch this space!

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