Wednesday, November 18, 2015

Uncertain Health in an Insecure World – 65


There is no human disease more feared than cancer in kids.

And among pediatric oncologists, there is no cancer more feared than childhood acute lymphoblastic leukemia (ALL). A rare disease, ALL affects 3,000 young persons in the U.S. annually, often beginning with fever and bruising, but quickly turning fatal if not aggressively treated at a specialized children’s hospital. After a bone marrow aspiration confirms the diagnosis, treatment involves complex chemotherapy, irradiation and stem cell transplant regimens. A shared sense of urgency to improve childhood leukemia mortality has created novel ALL therapies, which have turned around its poor prognosis into 98% remission and 90% ten-year survival rates at leading pediatric cancer centers.

Researchers are now borrowing upon this pediatric oncology urgency to promote precision medicine (PM) in other diseases.

Some ALL patients have the Philadelphia chromosome mutation (above), described in 1960 by Peter Nowell and David Hungerford at the University of Pennsylvania (below), who made the first direct link between a chromosomal abnormality and any malignancy. Recent research from the U.S. Pediatric Genome Project shows other gene mutations in the most deadly ALL subtype, early T-cell precursor (ETP), which may direct future PM tailored therapies.

Bert Vogelstein’s 2013 Science article describes the “march of mutations” through a genomic landscape which is the backdrop to the most common human cancers. Its “mountains” are genes altered in a high percentage of tumors (below), while the “hills” are infrequently altered genes. Over 140 cancer driver gene mutations have been described, with tumors typically expressing between two to eight such genes responsible for cell death, cell survival and healthy genome maintenance. Vogelstein’s construct of the diverse cancer genome is fostering the development of precisely targeted therapies.

In Boston last week, Siddhartha Muhkerjee (below), the author of The Emperor of All Maladies: A Biography of Cancer, spoke of his acute leukemia experiences as a pediatric cancer physician. He described how the human body “slouches towards cancer”, from one gene mutation to another. At a cellular level, even seemingly similar cancers differ from every other cancer in terms of their genetics and cell metabolism.

Fair warning from Sid – cancer biology is complex.

It includes organismal features – the physiology that keeps cancer cells alive; environmental features – the immunologic systems causing cancer cell destruction; and epigenetic features – the mechanisms that control cancer gene transcription into messenger RNA (mRNA).

Cancer is a “pathway disease.

Along the path to cancer (above), there are multiple switches opening and shutting cellular circuitry that largely exists like a massive iceberg below the water surface. New therapies must precisely target this submerged iceberg using personalized medicine approaches that are actionable.

Endogenous cellular sources of oxidative DNA damage via base pair and nucleotide excision – so-called single nucleotide polymorphisms or SNP’s – cause gene toxicity (i.e., genotoxicity) by inducing mutations in tumor-causing oncogenes and in tumor suppression genes. Exogenous viruses and chemical carcinogens can also promote mutations. 

The WHO’s International Agency for Research on Cancer (IARC, est. 1969) maintains a database on genotoxic and non-genotoxic carcinogens. Most carcinogens are also mutagens (i.e., changing human DNA). Of >900 likely candidates, some 100+ are classified by IARC as carcinogenic to humans. Because it takes years or decades for exposure to a carcinogen to cause cancer, making such cause & effect linkages can be complex. Landfills are quickly filling up with heavy metals and toxic chemicals that now permeate our ground water. But the last new human carcinogen was described >15 years ago, and only pre-natal ionizing radiation has been identified as a risk for ALL. 
Cells can be drugs, engineered and educated to attach to tumors and other benign diseases.

Synthetic biology can endow immune cells with new properties for treating ALL, and offers potential for treating some solid tumors. The widespread mutational burden of some diseases is a key to the success of a new class of immunotherapies called checkpoint inhibitors. Activated T-lymphocyes (T-cells) trying to kill tumor cells are neutralized when they attach to specific T-cell PD-1 or tumor cell PD-L1 receptors (above). This T-cell deactivation is prevented by the binding (below) of checkpoint inhibitors (i.e. Opdivo™ and Yervoy™ from Bristol Myers Squibb; Keytruda™ from Merck Sharp & Dohme), which have been effective in deadly metastatic melanoma, renal carcinoma and some lung cancers. It is feasible that similar approaches will work in the benign disease space and be used for tissue engineering.

Personalized medicine demands such precision.  
PM will not succeed if it is based on “n of 1” clinical trials. New drugs can only move forward into clinical use after phase-1/-2 safety studies are completed. The gold standard for phase-3 randomized clinical trial (RCT) informed treatment protocols is to balance therapeutic and toxic effects encountered in the average RCT study subject. But every cancer in every cancer patient is unique, so new “smart surrogate” clinical trials will be needed. PM-informed biological endpoints will replace standard RCT survival rates. So-called “basket trials” of regular cancer therapy plus T-cell activating/suppressing immunotherapy adjuvants are being designed.

Such molecularly-informed drug trials should always be guided by good clinical medicine.

The Roche Group acquired the remaining 40% of Genentech in 2009 for US$46.8B. On November 10, 2015 the FDA approved Cotellic™ (Roche-Genentech) for the treatment of BRAF V600E or V600K mutation-positive advanced melanoma (below), in combination with Zelboraf™. The phase-3 coBRIM study, started in 2012, combined Cotellic’s inhibition of MEK (a protein kinase like that above, phosphorylates the ERK gene regulating programmed cell death) and Zelboraf’s BRAF (a proto-oncogene making B-Raf protein that directs cell growth) in order to delay the onset of tumor resistance seen after BRAF inhibition alone. The endpoint used in this gene-targeted PM regimen was progression-free survival.

It worked!

Today, Roche-Genentech has >20 anti-cancer molecules (i.e., drugs) in its pipeline, and is committed to the treatment of children.

PM approaches are urgently needed for all cancers.

In July 2015, the National Cancer Institute (NCI) Molecular Analysis for Therapy Choice (MATCH) launched a nationwide phase-2 clinical trial to sequence the tumor biopsies of 3,000 patients, and match findings against a 143 cancer driver gene panel. NCI-MATCH (above) will bring diverse Big Pharma companies (including some that haven’t yet completed M&A transactions!; see post #63) together in PM-directed sub-studies to jointly develop novel clinical treatment protocols involving their otherwise proprietary blockbuster drugs.

We in the Square are heartened by all this urgency, and by the coming together of market competitors to extend the lives of our patients, not just their drug patents.

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