Sunday, May 13, 2012

Wanted: Targeted Drug Therapies

                        

              For our project, my partner and I are interested in why people who have survived a previous primary cancer are at a higher risk of developing a new, secondary primary cancer than people of the cancer naïve population developing a first cancer.  To attempt to answer this question, we are focusing on treatment that cancer patients commonly go through to try to eradicate their cancer.  Our hypothesis is that these treatments, such as radiotherapy and chemotherapy, will make the patient much more likely to develop a whole new cancer later in life.  Also, genetic factors may contribute to a predisposition for a second or third cancer developing later.  An example of this that we have discussed in class is familial retinoblastoma patients, who have inherited a defective copy of the Rb gene.  It is very common for these patients to develop secondary cancers in adolescence, particularly osteosarcomas.  It is still unknown why these patients primarily get retinal and bone tumors if the Rb gene operates in a wide variety of different tissues throughout the body (Weinberg 221).    
               
During my research, I found an interesting article about the increased incidence of secondary cancers in familial retinoblastoma survivors who received radiotherapy.   The researchers followed retinoblastoma patients diagnosed from 1914 to 1984 in two medical centers in New York and Boston.  They excluded from their cohort those that died within 12 months of diagnosis, died outside of the United States, or had an unknown birth year.  Of the 1,601 patients they studied, 60% had familial retinoblastoma with one or both eyes affected, while 40% had sporadic retinoblastoma with one eye affected.  The median year of diagnosis was 1966, therefore some of the patients had already died by the time they conducted their study.  80% of familial patients were treated with radiation for Rb, compared to only 18% of the sporadic patients.  
                From 1993 to 2000, the researchers identified 78 new primary cancers, one half of which were sarcomas.  The familial patients had a significantly higher incidence of secondary cancers, which was expected.  What is novel about this study is that they found that the risk of secondary cancer was elevated almost seven-fold in nonirradiated familial patients and radiotherapy further increased this risk by 3.1-fold.  This meant that the radiotherapy increased the high risk the familial patients already had of developing a new cancer later in life.  Furthermore, the highly irradiated sites had the highest incidence of new cancer (Table 4).  For example, since most familial patients treated with radiotherapy received it near their face and neck, cancer in the brain, nasal cavities, and eye were more common than moderately or lightly irradiated sites. 

Table 4. Risk of New Cancers in 1-Year Survivors of Hereditary Rb by Radiation for Rb
Figure 1. Cumulative Incidence and 95% Cls of new cancers by time since diagnosis of retinoblastoma by hereditary status.

                This study confirms the urgency to develop targeted drug therapy treatments to replace traditional treatments such as radiotherapy and chemotherapy, which can cause damage to normal cells, thereby increasing the risk of a new cancer.  An article written by Howard B. Lieberman describes how these therapies damage the DNA and what response systems are in place inside a cell to combat this damage.  At the end of his article, he proposes that DNA damage repair and response proteins can be used as targets for cancer therapy.  He theorizes that if drug therapies can target these DNA damage repair systems of the cancer cells, it will prevent the cancer cells from repairing their DNA and therefore become more likely to be eradicated.  Researchers could avoid the drug therapies from affecting normal cells by only targeting defective proteins or pathways that are utilized in cancer cells only.  For example, cancer cells are genetically unstable and consequently may have a deficiency in DNA repair systems.   Therefore, the cancer cells may rely on backup repair processes that normal cells do not have to resort to since their primary process is still intact.  If these backup pathways could be pinpointed, they could also be targeted for inactivation so the cancer cells cannot repair DNA.  A therapy like this would make chemotherapy and radiation more effective against cancer while protecting normal cells from damage.  Many cancer cells are mutated in the BRCA1 or BRCA2 genes; this makes the cell rely on other pathways such as NHEJ or BER to fix certain types of DNA damage.  In this example, the NHEJ or BER pathways would be targeted. 
                Overall, I think this is an interesting proposal for solving some of the problems of chemotherapy and radiation and should be considered.  It would require a lot of time spent genetically profiling the cancer cell as compared to the noncancerous cells so that they are sure the drug will not target the normal cells.  What do you think?  Should we try to modify these traditional forms of therapies or focus our attention on completely new, independent targeted drug therapies that would target RTKs, for example?