Our Focus

Understanding Genetic Alterations

Protein Man

Understanding Genetic Alterations

Proteins and DNA

The human body is primarily composed of proteins, which are large molecules that can perform many functions for skin, muscle, hormones and thousands of other specialized activities.

Proteins themselves are composed of strings of some combination of the same twenty amino acids, connected like beads on a necklace.

The sequence of the beads (amino acids) determines how the necklace (protein) folds on itself, reacts with water and takes on a shape or function that gives it its unique abilities.


How does any given cell know how to make a protein?

It reads the instructions from the source code of DNA (deoxyribonucleic acid), which operates as a blueprint of biological guidelines that a living organism must follow to remain functional.


DNA

DNA

DNA itself is comprised of four nucleotide building block "bases" shortened as

A, T, C and G.

Every human cell contains DNA comprising approximately 6 billion of these bases. In order for a cell to make protein from this DNA code, the DNA is first changed to a sister code called RNA (ribonucleic acid), which contains a similar four-letter coding system.


RNA

RNA

The different RNA letters make up unique three-letter words called

codons

Codons tell the cell how to order the 20 amino acids in the proper order so that the right protein is made. Individual cells in the body pay more attention to certain sections of the DNA than others. For example, a cell in the stomach may pay more attention to the DNA instructions that code for gastric acid, while ignoring the instructions that encode for hemoglobin.


Alterations

Alterations in the DNA code, such as changing a letter, deleting a letter, inserting a letter or moving sections around can lead to proteins with abnormal functions.

If these abnormal functions cause the cell to grow, divide, ignore regulatory signals or assume new functions, cancers can develop.

Fortunately, normal cells are good at repairing mistakes should they occur, and have multiple systems for ensuring that the DNA code is properly transmitted to its two daughter cells when it divides. Normal cells even have suicide programs if the mistakes are beyond repair, a process that causes cell death, known as apoptosis.


Passenger vs. Driver Alterations

Cancer cells typically harbor DNA changes, or more technically, genetic alterations. However, not all genetic alterations are created equal. A key challenge for drug developers like Loxo Oncology is distinguishing between genetic alterations that “drive” the growth of tumors versus “passenger” alterations, which result from the underlying genetic instability of the cancer.

The automobile references acknowledge that drivers make a car go, while passengers are merely along for the ride. If, by analogy, the cancer cell is an out of control car, targeting the driver not the passenger is the best way to stop the vehicle.


Types of Genetic Alterations


Cancer cells typically harbor DNA changes, or more technically, genetic alterations.  

However, not all genetic alterations are created equal. A key challenge for drug developers like Loxo Oncology is distinguishing between genetic alterations that “drive” the growth of tumors versus “passenger” alterations, which result from the underlying genetic instability of the cancer. The automobile references acknowledge that drivers make a car go, while passengers are merely along for the ride. If, by analogy, the cancer cell is an out of control car, targeting the driver not the passenger is the best way to stop the vehicle.

  • Gene Fusion

    Gene fusions occur when chromosomes, which carry genetic information, break apart and the wrong pieces fuse back together, forming a hybrid gene that can activate a signaling pathway, or a way cells communicate with each other.

  • Mutation

    Mutations are the result of a defect in one of the four nucleotide building block “bases” that create DNA. The human genome contains over six billion nucleotides.

  • Amplification

    Amplifications are when too many copies of a gene lead to an abnormal amount of protein being produced. Ultimately, the cell can acquire abnormal growth and survival behaviors leading to cancer.

  • Protein Overexpression

    Protein overexpression occurs when a cell produces abnormally high amounts of protein from the DNA and RNA building blocks.

Gene fusions occur when chromosomes, which carry genetic information, break apart and the wrong pieces fuse back together, forming a hybrid gene that can activate a signaling pathway, or a way cells communicate with each other. When this happens in a cancer cell, the fused gene is like a light switch that’s always in the “on” position, causing tumor growth. Research suggests that gene fusions have a very high likelihood of being driver events in cancer due to the dramatic genetic change that occurs in the cancer cell.

Mutations are the result of a defect in one of the four nucleotide building block “bases” that create DNA. The human genome contains over six billion nucleotides. Small changes, deletions or insertions in a gene’s nucleotide sequence can change the functional behavior of the final protein, leading to cancer. However, sometimes a mutation has no functional effect on the final protein. Most cancers simply have hundreds of accumulated mutations that don’t play an active role in tumor cell proliferation (the rapid reproduction of cells).

At Loxo Oncology, we aim to help determine the “driver” mutations vs. the “passenger” mutations in order to best predict which patients may derive benefit from our drugs.

Amplifications are when too many copies of a gene lead to an abnormal amount of protein being produced. Ultimately, the cell can acquire abnormal growth and survival behaviors leading to cancer. Amplifications do not always cause cancer because in some cases the gene amplification does not lead to protein overexpression or the number of extra copies is relatively small. It is important to understand which amplifications may predict patient benefit from our drugs.

Protein overexpression occurs when a cell produces abnormally high amounts of protein from the DNA and RNA building blocks. Depending on how much of the protein exists in the cancer cell and the context in which the protein is overexpressed, this can indicate that the protein is causing the cancer.


Our lead therapy, larotrectinib (LOXO-101) is being developed as a targeted cancer therapeutic for tropomyosin receptor kinase (TRK) genetic alterations, focused initially on patients harboring TRK gene fusions.

TRK consists of a family of three cell receptor proteins known as TRKA, TRKB, and TRKC, which are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. Under normal conditions, TRK receptors are found primarily in nerve cells. TRK receptors become activated when they bind to proteins circulating outside the cell (such proteins are referred to as ligands). For TRK, the activating ligands are collectively referred to as neurotrophins. Neurotrophins bind to TRK receptors, causing activation of a kinase signaling pathways of kinases. These signaling pathways help regulate how neurons function in the setting of pain, cognition, movement, memory, and mood.

When an TRK gene abnormally fuses to another gene, the hybrid gene that is created as a result causes this process to go awry, leading to cancer and driving tumor growth. These gene fusions no longer require the neurotrophins to become activated; instead, they are constantly active simply as a result of the gene fusion event. Our clinical trials are intended to help understand if LOXO-101 can be a safe and effective therapy for patients whose tumors harbor this TRK fusion genetic event.

Patients with advanced cancer who seek out tumor profiling or comprehensive cancer genetic testing may discover that their tumor harbors a TRK fusion, as this genetic event has been described across many tumor types, including:

  • acute myeloid leukemia
  • astrocytoma
  • brain low-grade glioma
  • breast cancer
  • colorectal cancer
  • congenital mesoblastic nephroma
  • gastrointestinal stromal tumors
  • glioblastoma multiforme
  • head and neck squamous cell cancer
  • intrahepatic cholangiocarcinoma
  • lung cancer
  • mammary analogue secretory carcinoma of salivary gland origin
  • melanoma
  • sarcoma
  • secretory breast cancer
  • thyroid cancer

Read more about TRK alterations in the following publications:


The rearranged during transfection (RET) receptor is a tyrosine kinase receptor that binds the glial cell line-derived neurotrophic factor (GDNF) ligand family and contributes to the development of the nervous system and kidneys. Activating fusions and mutations in RET have been identified across a range of cancer types, including lung, thyroid and colon.

Loxo Oncology has developed LOXO-292, a highly specific RET inhibitor designed to optimize on-target potency for RET fusions, activating RET mutations and anticipated resistance mutations. Loxo Oncology plans to initiate clinical development of LOXO-292 in early 2017. Click here to read more about LOXO-292.


The fibroblast growth factor receptor (FGFR1-4) family of tyrosine kinases plays an important role in normal physiologic processes of the body, including angiogenesis, wound healing and regulation of calcium and phosphate metabolism. In addition, abnormal FGFR signaling through genetic alterations or altered expression of individual receptors has been frequently observed in human tumors.

Gene fusions, activating mutations and high-level gene amplifications have been identified in multiple tumor types including bladder, kidney, endometrial, brain, breast and pancreatic cancers.