Overview: Oncology – Liquid Tumors (Hematological Malignancies)

Hematological malignancies, such as leukemia and lymphoma, are cancers that affect the blood, bone marrow, and lymph nodes. In recent years, the incidence of hematological malignancies has steadily increased in the United States (U.S.) and is expected to account for 10 percent of new cancer cases diagnosed in the U.S. in 2019.1

The Wnt pathway is a primary physiological regulator and signaling pathway that controls the activity of stem cells. These specialized cells have the unique ability to self-renew and form multiple cell types and tissues.2 Hematopoiesis is the process in which stem cells develop into mature blood cell components. The Wnt signaling pathway has been shown to have an effect on controlling the proliferation, survival, and differentiation of hematopoietic cells.3 Altered expression or activity of various Wnt pathway components through DNA mutations or epigenetic changes (without gene mutation) in stem or normal cells can cause Wnt signaling to be inappropriately activated, resulting in transformation, proliferation, and replicative immortality of cells.2,4 Therefore, this pathway, which is normally tightly regulated, can become hijacked in malignant tumors and contribute to cancer development and progression.2,4,5 As evidence of this, aberration of Wnt pathway proteins is detected in many hematological cancer patients.6 Therefore, modulation of the Wnt pathway with small-molecule drugs offers a potential therapeutic option for the treatment of hematological malignancies.

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Risk factors include advanced age, genetic disorders, and smoking and high exposure to radiation, chemotherapy, or toxic chemicals.7

  • There will be an estimated 21,450 newly diagnosed U.S. cases of AML in 2019, mostly in adults.8
  • AML will be responsible for an estimated 10,920 U.S. deaths in 2019, almost all in adults.8
  • For adults who are 20 years of age and older, the five-year relative survival rate is 24%.9

Wnt signaling pathway activation has been implicated in AML development and progression.10-13

  • Studies have shown that β-catenin, a proto-oncogene and key component of the Wnt signaling pathway, is overexpressed in the blood cells of more than half of patients diagnosed with AML compared to individuals without AML.10,11
  • Multiple studies have shown that epigenetic alterations resulting in the inactivation of Wnt signaling pathway inhibitors contribute to AML.12,13

Mantle Cell Lymphoma (MCL) is a less common form of non-Hodgkin B-cell lymphoma that is frequently aggressive and incurable. MCL occurs more often in men than it does in women.14 Though the exact cause of MCL is unknown, people are usually diagnosed in their 60s.14

  • Each year, there are an estimated 4,300 new cases of MCL in the U.S.15
  • The median overall survival of individuals with MCL is 4 to 5 years after diagnosis.16

Evidence suggests that the Wnt signaling pathway is involved in the development of MCL.17,18

  • Activated Wnt signaling has been found in MCL and appears to promote tumor cell growth.17
  • In vitro pharmacological inhibition of Wnt signaling was effective at eliminating a subpopulation of MCL-initiating cells implicated in MCL resistance to chemotherapy.18

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non‐Hodgkin lymphoma (NHL). DLBCL is the most commonly diagnosed type of NHL worldwide and represents approximately 22% of new NHL cases in the U.S. each year.19,20 Potential risk factors for DLBCL include underlying illnesses or medications that lead to immunosuppression, ultraviolet radiation, pesticides, certain hair dyes, and diet.21

  • Each year, more than an estimated 18,000 individuals are diagnosed with DLBCL in the U.S.22
  • The five-year relative survival rate for DLBCL is approximately 63%.23

Substantial evidence suggests that Wnt signaling pathway alterations contribute to DLBCL tumorgenicity.24-26

  • Dual expression of the anti-apoptotic protein BCL-2 and MYC, a Wnt target gene27, was predictive of poor survival in DLBCL patients.24,25
  • Wnt signaling pathway mutations were demonstrated in primary DLBCL tumor samples.26

References

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    15. https://www.lls.org/sites/default/files/file_assets/FS4_MCL_Facts_2018-final.pdf
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