Cancer continues to be a formidable adversary of modern medicine. The American Cancer Society predicts that in 2023, the United States will see approximately 1.9 million new cancer diagnoses and 610,000 cancer-related deaths.

Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.

Despite efforts to advance anti-cancer treatments, their clinical efficacy remains hampered by toxic side effects and drug resistance. 

 

Metastasis, the hallmark of malignant cancers, occurs despite obstacles that the cancer encounters as it spreads to different organs, due to the stress experienced by tumor cells. A group of genes known as “cancer fitness genes” or “metastasis fitness genes” assist in overcoming these challenges, as reported in a review published by Genes and Development.

Shen M, Kang Y. Stresses in the metastatic cascade: molecular mechanisms and therapeutic opportunities. Genes Dev. 2020;34(23-24):1577–1598.

 

 

 

What are cancer fitness genes?

Cancer fitness genes are a unique category of genes expressed by cancer tissue that play a pivotal role in its progression—but are not necessary for the initial development of the tumor or its malignant transformation.

A review published by Trends in Cancer discusses the features and function of cancer fitness genes.

Shen M, Kang Y. Cancer fitness genes: emerging therapeutic targets for metastasis. Trends Cancer. 2023;9(1):69–82. 

 

The three most widely researched are the L1 cell adhesion molecule (L1CAM), metadherin (MTDH), and notch ligand jagged1 (JAG1). Other examples include XIAP, DSC2, NGFR, SPARC, LOXL2, PD-L1, TRIB3, CD133, FUT4, CD112, CD155, and LGALS9. Interestingly, none of these genes is expressed in healthy tissue. 

 

Cancer fitness genes maintain cancer stem cell activity, promote survival under stress, shield tumor cells from the immune system, and make them chemoresistant. 

For example, the gene MTDH promotes disease progression, metastasis, and drug resistance in advanced breast, prostate, and colorectal carcinoma.

Other cancer fitness genes like XIAP and SPARC inhibit apoptosis and promote chemoresistance, while DSC2 increases metastasis relapse. 

 

Cancer fitness genes vs driver oncogenes

 

For starters, driver oncogenes are often not required for maintaining cancer progression or metastasis in advanced tumors. Moreover, these oncogenes are crucial for normal physiologic functions—playing a role in normal processes like chemotaxis, embryo development, trafficking immune cells, and even shaping how neurons connect.

When used for targeted chemotherapy, cancer fitness genes overcome the limitations of driver oncogenes in several ways:

• Unlike conventional oncogenes, cancer fitness genes are not responsible for gene mutations or transformations in the early stages. 

• However, just like oncogenes, they are frequently overexpressed in advanced stages.

• Inhibiting or genetically knocking out cancer fitness genes can significantly reduce tumor progression and the development of distant metastases. 

• Yet, the altered activity of cancer fitness genes does not interfere with normal physiological processes. 

Hence, although cancer fitness genes don't conform to the classic definition of oncogenes, they are still rational targets for cancer therapy.

 

Targets for chemotherapy

 

Chemotherapy targeting cancer fitness genes could also be effective for late-stage metastatic carcinoma. The following are a few successful examples as cited by the investigators publishing in Trends in Cancer:

1. Pharmacologic inhibitors of MTDH—including drugs like antisense oligonucleotides (ASOs) and small-molecule inhibitors—make metastatic breast cancer sensitive to chemotherapy (mouse model).

2. Following their success in in-vitro models, XIAP inhibitors, like ASOs and Debio 1143 (a small-molecule inhibitor of XIAP), have also shown promising results in pre-clinical and clinical trials (leukemia, pancreatic cancer, hepatocellular carcinoma).

   Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: A double-blind, multicentre, randomised, phase 2 study. MDLinx. August 2020.

    

 

Tumor immune surveillance

 

Researchers are targeting cancer fitness genes to enhance tumor surveillance and make immune checkpoint inhibitors more effective. Antibodies targeting JAG1 and galectin-9 have been developed and are in preclinical or clinical trials.

LYT-200 Alone and in Combination With Chemotherapy or Tislelizumab in Patients With Locally Advanced or Metastatic Solid Tumors. Clinicaltrials.gov. December 2020. NCT04666688.