Personalizing cancer treatments via genetics

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Posted: 09/19/2017

Human Genetics Scientist,  Joyce El Hokayem, continues her discussion on innovations within cancer treatment.

Read her first post here Exciting elixirs in the oncology pipeline

As we know, cancer is a very complex and variable disease. It is very well established that solid tumors differ dramatically from one organ to another and from one transformed cell type to another that are susceptible to cancer within a particular tissue or organ.

This variability is clear at different levels: genetically, chromosomally, histologically, physiologically, pathologically, and in terms of prognosis.

However, personalized cancer medicine helps doctors to know more about a person’s genetic constitution and how their tumor is growing. In this way, it will help doctors to find prevention, screening, and treatment strategies that may be more effective. They also want to find treatments that cause fewer side effects. In order to customize the treatment to each patients needs, doctors are performing genetic tests on the cancer cells versus on normal cells.

Building a personalized screening and treatment plan

When creating a personalized screening and treatment plan, firstly,  doctors must find out the chances of a patient to develop cancer and choose the best screening strategies to lower the risk.

Then, patients are matched with appropriate treatments ­­– those which are the most effective and cause less side effects.

Finally, the risk of recurrence must be predicted, in other words, determining the chances that might lead the patient to relapse.

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Targeted therapies help to stop the cancer to grow and spread in the whole body. This is only possible by targeting specific genes or proteins in cancer cells or in cells related to cancer cell growth.

Personalized Cancer Therapy

There are two main types of targeted therapy:  monoclonal antibodies that have been established as one of the most therapeutic strategies for both hematologic malignancies and solid tumors in the last 20 years. Also,  small molecule drugs that can easily enter the cell because it has a low molecular weight comparing to the monoclonal antibodies that have large molecular weight.

The aim of the small molecule drugs is to affect some proteins inside the cell and kill the tumor cell. For instance, angiogenesis inhibitors starve the tumor by preventing new blood vessels from developing because the tumor needs the blood vessels to bring its nutrient.

Ramucirumab (Cyramza) is used to treat advanced stomach cancer and gastroesophageal junction adenocarcinoma. This is a form of cancer located where the stomach joins to the esophagus. This drug is also used for colorectal cancer and non-small cell lung cancer.

Recent developments: personalized pancreatic cancer therapy

Another example showing the promise of personalized cancer medicine can be seen in recent breakthroughs regarding pancreatic ductal adenocarcinoma (PDAC)   ­– the world’s most lethal cancer, with a 5-year survival of 5%, a figure unchanged in the last 50 years.

PDAC is defined by marked genetic heterogeneity, recent genomic sequencing has demonstrated that with the exclusion of known mutations in these genes KRAS, TP53, SMAD4, CDKN2A, most mutations occur at a prevalence of <5%. Nevertheless, these can be grouped into 14 main signaling pathways [1].

The study applied innovative genomics techniques : Whole Exome Sequencing and Copy Number Variation, and data for 100 patients with PDAC revealed activated mutations of KRAS in >90%. Although loss of function events of tumor suppressors predominate, a variety of secondary gain of function events occur in genes that are known drivers of carcinogenesis in other cancer types.

This means that even though KRAS is involved in the early stage of PDAC evolution, a second gain of function event might be required for progression. This has important implications for therapy.

Today, the only well known treatment for pancreatic cancer is the surgical resection, which is only viable to less than 20% of those diagnosed.

Chemotherapy is used to avoid patient relapses, but there is no guarantee for a total curation.

Some pancreatic cancer immunotherapies have shown promising results, but only in early-stage clinical trials. The likes of which include checkpoint/inhibitors, monoclonal antibodies, oncolytic viruses, adoptive cell transfer, therapeutic vaccines, adjuvant immunotherapies and cytokines.

Due to the lack of airtight treatment options in this area of oncology, personalized pancreatic cancer therapy is required.

In her next and final article in this series Joyce will review the subject of DNA mutations and their role in triggering cancer.

Sources: 
1-     Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321(5897):1801-6 

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Posted: 09/19/2017

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