Technology Focus

Selective Inhibition of Nuclear Export

Since its founding in 2008, Karyopharm has been an industry leader in oral Selective Inhibitor of Nuclear Export (SINE) technology, developed to address a fundamental mechanism of oncogenesis: Nuclear Export Dysregulation.

The following is a high-level description of how this fundamental mechanism is thought to work:

  • Tumor suppressor proteins monitor DNA inside of a cell’s nucleus and look for damage — a hallmark of cancer.
  • When tumor suppressor proteins identify DNA mutations, they signal core mechanisms that prevent cancer cells from growing in our bodies. (1-3)
  • Many tumor suppressor proteins can only function properly when they are located inside of a cell’s nucleus.
  • One way cancers evade detection from the body’s own defense mechanisms is by removing these tumor suppressor proteins from within the cell nucleus via an overproduction of a specific chaperone protein called Exportin 1 (XPO1).
  • Additionally, there are other important proteins, including those that help regulate cell growth and inflammation, that are also depleted from a cell’s nucleus when there is an over-expression of XPO1.
  • Karyopharm’s drug candidates inhibit XPO1 which may restore the cell’s core natural anti-cancer defenses.

The Process Defined

See below to learn more about how dysregulated nuclear export can allow tumors to proliferate and survive and how targeting this pathway may lead to advances in cancer care.

Normal, Healthy Cell Behavior

A human cell is divided into various compartments, including the nucleus and the cytoplasm. The nucleus contains a cell’s genetic material, or DNA, and is the compartment where gene expression is regulated.

The cytoplasm is the compartment around the nucleus where translation of gene transcripts, or mRNA, to proteins, assembly of proteins into cellular structural elements, and cellular metabolism of fats, carbohydrates, and proteins, occur.

When tumor suppressor proteins identify DNA damage, these proteins help signal for repair mechanisms, or if the damage is too severe, programmed cell death through a process called apoptosis.
This is one of the core mechanisms that help us all prevent cancers from growing in our bodies. (1-3)

Additionally, other important anti-oncogenic proteins, including growth regulatory and anti-inflammatory proteins, need to be localized in the nucleus to carry out their primary functions.

Normal XPO1 Expression

The Nuclear Pore and the XPO1 Protein

The nuclear pore is a complex gate between the nucleus and cytoplasm, closely regulating the import and export of most large molecules, including many proteins. In healthy cells, transport through the nuclear pore is tightly regulated and requires specific carrier proteins, called importins or exportins, to occur. In humans, there are seven known exportins, or nuclear export proteins. The most well-characterized is called Exportin 1, or XPO1.

XPO1 appears to be the only nuclear exporter for key tumor suppressor proteins, including those generally referred to as p53, p73, FOXO, pRB, BRCA1, and PP2A, which have been well-characterized in cancer research.

How XPO1 Helps Some Cancer Cells Develop and Evade Detection

Cancer is a disease characterized by unregulated cell growth. Cancer typically develops when DNA becomes disrupted or damaged. Sometimes this DNA damage leads to an overproduction of proteins that regulate cell growth and division. And sometimes this DNA damage leads to the disabling of the cell’s natural anti-cancer mechanisms.(1,2,4)

While there are often multiple cellular mechanisms functioning improperly in cancer cells, the dysregulation of nuclear export appears to be a very important driver of some cancers.(1,4)

Many cancer cells evolve and evade the body’s own defense mechanisms by overproducing XPO1, thereby, reducing levels of important anti-oncogenic proteins from within the cell’s nucleus.

XPO1 levels have been shown to be elevated in cancer cells compared to their normal cell counterparts. It appears that cancer cells have co-opted XPO1 to move tumor suppressor proteins out of the nucleus, thereby adversely affecting their ability to identify and initiate the death of cancer cells.

Increased levels of XPO1 in cancer cells also lead to excessive nuclear export of growth regulatory proteins and allow cancer cells to grow and divide uncontrollably. Higher levels of XPO1 expression have also been correlated with poor prognosis and/or resistance to anti-cancer mechanisms in some cancers. 5,6,7

Overexpression
Inhibition

Targeting Nuclear Dysregulation as an Approach to Treating Cancer

Karyopharm’s lead investigational drug candidates are first-in-class, oral, selective inhibitors of XPO1.

XPO1 inhibitors block the nuclear export of tumor suppressor, growth
regulatory, and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion.

Importantly, healthy cells also build up tumor suppressor proteins in the presence of a SINE compound but do not undergo apoptosis and are able to resume normal activity after transient XPO1 inhibition because they have an intact genome with minimal or no DNA damage.

Our first drug which targets the XPO1 protein received accelerated approval from the FDA in July 2019 for the treatment of patients with heavily pretreated relapsed refractory multiple myeloma and accelerated approval from the FDA in June 2020 for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. In December 2020, it received FDA approval as a treatment for patients with multiple myeloma after at least one prior therapy.

References

  1. Gupta A, Saltarski JM, White MA, Scaglioni PP, Gerber DE. Therapeutic targeting of nuclear export inhibition in lung cancer. J Thorac Oncol. 2017;12(9):1446-1450.
  2. Sun Q, Chen X, Zhou Q, Burstein E, Yang S, Jia D. Inhibiting cancer cell hallmark features through nuclear export inhibition. Signal Transduct Target Ther. 2016;1:16010.
  3. Mor A, White MA, Fontoura BM. Nuclear trafficking in health and disease. Curr Opin Cell Biol. 2014;28:28-35.
  4. Gandhi UH, Senapedis W, Baloglu E, et al. Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18(5):335-345.
  5. Kojima K, Kornblau S, et al. Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood. 2013;121(20):4166-4174.
  6. Tai Y, Landesman Y, et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia. 2014 January; 28(1): 155–165.
  7. Yoshimura M, shizawa J, et al. Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma. Cancer Sci. 2014;  105 (7): 795–801.
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